Abstract
The sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein)). This protein has been linked to diseases and conditions such as Niemann-Pick disease, schizophrenia, neuropathic pain, traumatic brain injury, cancer, drug addiction, and Alzheimer’s disease. The therapeutic utility of σ2 ligands is under investigation in numerous laboratories and on-going clinical trials. Herein, we report the identification of a series of novel 5-(2-(5-arylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-γ-butyrolactone and their evaluation using in vitro σ2 and sigma-1 (σ1) assays to determine their σ1/σ2 selectivity profiles, as well as a series of in vitro ADME assays.
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Introduction
The observation by W. R. Martin et. al. that Morphine, ketocyclazocine, and SKF-100047 produced different responses in chronic spinal dogs led them to propose that each compound was interacting with a different pharmacological target. They designated the three targets the µ-opioid receptor (morphine type, MOR), the κ-opioid receptor (ketocyclazocine type, KOR), and the σ-opioid receptor (SKF-100047 like) [1]. It was eventually determined that two enantiomers of SKF-100047 engage different targets. While (-)-SKF-100047 interacts with MOR and KOR to elicit an opioid-type response, (+)-SKF-100047 produces a non-opioid response through the sigma receptor (σR) [2, 3]. There are two sub-types of this receptor, designated sigma-1 (σ1) and sigma-2 (σ2) [4]. Crystal structure for both have been reported [5, 6], but date no natural ligands have been identified.
It was recently demonstrated that σ2 is identical to the protein designated Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein)) [7]. This protein is present in the endoplasmic reticulum (ER) and lysosomes where it binds to cholesterol [8] and has been linked to Niemann-Pick disease [9], schizophrenia [10], neuropathic pain [11, 12], traumatic brain injury [13], cancer [14, 15], drug addiction [16], and Alzheimer’s disease [17, 18]. The recent disclosure that σ2 ligands can prevent the synaptotoxic impact of Aβ oligomers (AβO, oligomers of Aβ42) on neurons by blocking their interactions with neuronal receptors suggests that σ2 may be a viable therapeutic target for the treatment of Alzheimer’s disease [19]. The clinical candidate CT1812 (1, Fig. 1), a high affinity σ2 ligand (Ki = 8.5 nM) that is moderately selectivity for σ2 over σ1 (σ1 Ki = 63 nM) and has demonstrated efficacy in the hAPP Swe/Ldn mouse model of Alzheimer’s disease, is currently undergoing phase 2 trials and will test this possibility [20]. Separately, the utility of this target in the diagnosis and treatment of breast cancer is currently under clinical investigation using [18F]ISO-1 (2, Fig. 1), a radioligand with high σ2 affinity (σ2 Ki = 6.9 nM). This compound displayed a high level of σ1/σ2 selectivity (σ1 Ki = 330 nM, σ1/σ2 = 47.8) [21]. Other σ2 ligands have also produced positive results in animal models of pain [11, 22], depression, anxiety, [23], and drug addiction [16].
The possible utility of σ2 ligands in numerous disease states prompted us to launch a program focused on the identification of novel σ2 ligands. We recently reported a series of functionalized γ-butyrolactone σ2 ligands typified by (3, Fig. 1). This compound demonstrated moderate σ2 affinity (Ki = 82 nM) as well as affinity for the related protein σ1 (Ki = 138 nM) [24]. As part of an effort to expand this series of novel σ2 ligands, we opted to explore potential piperazine bioisosteres. We specifically focused on replacing the piperazine ring (4) with a octahydropyrrolo[3,4-c]pyrrole moiety (5) [25]. As noted in Fig. 2, these ring systems are similar in that they are both diamines, but their 3-dimensional shapes and the distance between the amines of each ring are substantially different. While the piperazine ring (4) exists in a standard chair configuration and has a nitrogen/nitrogen interatomic distance of 2.85 Å, the octahydropyrrolo[3,4-c]pyrrole ring system (5) exists in a distorted chair configuration and has a much larger nitrogen/nitrogen interatomic distance (4.38 Å). In addition, while the piperazine (4) nitrogen loan pairs of electrons are oriented parallel to each other and close enough to interact through space, this is not the case with the octahydropyrrolo[3,4-c]pyrrole ring system (5). The loan pairs of electrons in the later ring system are oriented away from each other and farther apart, which limits through space interactions. We hypothesized that these differences could lead to altered σ2 affinity and selectivity for σ2 over σ1. The synthesis, characterization, and evaluation of a series of 5-(2-(5-arylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-γ-butyrolactone as potential selective σ2 ligands will be presented.
Results and discussion
Synthesis of target compounds is described in Schemes 1–3. The synthesis of (11a)–(11l) (Scheme 1) begins with the known alcohol (6) [24] which was Scheme 1: Synthesis of (11a)–(11l) converted to the corresponding bromide (7) with CBr4 and PPh3 in THF. Separately, aryl bromide (8) was reacted with Boc- or benzyl protect octahydropyrrolo[3,4-c]pyrrole (9) under Buchwald conditions to provide the protected aryl octahydropyrrolo[3,4-c]pyrrole (10). Deprotection of (10) either under acidic conditions (TFA/CH2Cl2 or HCl/MeOH) or via hydrogenation provided the free amine which was then reacted with (7) under basic conditions and with microwave heating to provide final target compounds (11a)–(11l).
The three phenolic targets, (11m)–(11o), were prepared according to the methods described in Scheme 2. Bromophenol (12) was initially converted to the benzyl ether under basic conditions, and the resulting product was reacted with Boc-protect octahydropyrrolo[3,4-c]pyrrole (9) under Buchwald conditions to provide aryl octahydropyrrolo[3,4-c]pyrrole (13). Removal of the Boc-group under acidic conditions (TFA/CH2Cl2 or HCl/MeOH), provided the corresponding free amine which was reacted with (7) under basic condition and then subjected to Pd/C catalyzed hydrogenation to provide target compounds (11m)–(11o).
The pyridine analog (11p) was prepared according to the method of Scheme 3. Bromide (7) was reacted with benzyl protected octahydropyrrolo[3,4-c]pyrrole (14) under basic conditions to provide (15). Removal of the benzyl protecting group via hydrogenation provided the free amine, which was then reacted with 4-Br-pyridine HCl under basic conditions to provide the target compound (11p).
Table 1 describe the in vitro binding (Ki at σ1 and σ2), physicochemical properties (MW, TPSA, LogP), solubility, and CYP450 activity (3A4, 2D6, 2C9) of (11a)–(11p). All of the compounds are consistent with Lipinski’s rule of 5 (MW, cLogP) and have acceptable water solubility (60–200 µM). In addition, TPSA and cLogP of the compounds are in a range that is indicative of BBB penetration (TPSA < 90, cLogP = 2–4) [26] except for (11h) whose cLog is outside of this range (cLogP = 4.8).
The structure activity analysis of this series begins with a comparison of the piperazine parent compound (3) with the corresponding octahydropyrrolo[3,4-c]pyrrole analog (11a). This biosiosteric replacement led to a >20-fold increase in σ2 affinity (11a σ2 Ki = 3.5 nM) and a smaller increase in σ1 affinity (11a σ1 Ki = 31 nM, 8.9-fold selectivity). Incorporation of a cyano substituent in the 2-, 3-, or 4-positions (11b-11d) produced compounds with similar σ2 affinity (σ2 Ki = 6.8, 7.0, and 9.6 nM respectively), but σ1 affinity also increased (σ1 Ki = 20, 22, and 22 nM respectively) and selectivity decreased to 3.1–2.3-fold. Replacing the cyano substituents with a CH3 (11e-11g) once again produced compounds with high affinity for σ2 (Ki = 2.4, 3.7, and 8.3 nM respectively), but selectivity over σ1 diverged. While the 2-CH3 analog (11e) exhibit low selectivity for σ2 over σ1 (σ1 Ki = 8.5 nM, 3.5-fold selectivity), the 3-CH3 analog (11f) and 4-CH3 analog (11g) were substantially more selective. In each case, >10-fold selectivity for σ2 over σ1 was observed (11f σ1 Ki = 39 nM, 11g σ1 Ki = 86 nM). Interestingly, increasing the size of the substituent in the 2-position by replacing the CH3 with an isopropyl group (11h) led to increased σ2 selectivity. Binding affinity at σ2 was maintained (Ki = 2.0 nM), but σ1 potency decreased by >3-fold (σ1 Ki = 31.6 nM) in comparison to the 2-CH3 (11e) analog and selectivity increased (15.8-fold). Incorporation of a morpholine ring in the 2-position (11i) also provided a high affinity σ2 ligand (Ki = 6.3 nM), and σ1 potency decreased (Ki = 47 nM).
Incorporation of a methoxy (11j-11l) or a hydroxy (11m-11o) moiety on the benzene ring led to divergent results. Lower σ2 affinity was observed when a methoxy moiety was placed in the 3- or 4-positions (11k, 11l, σ2 Ki = 25 and 22 nM respectively) and selectivity over σ1 was low (1.9-fold and 2.8-fold). The 2-OMe analog (11j), on the other hand, remained a single digit nM ligand for σ2 (Ki = 6.5 nM), but σ1 affinity drop significantly (Ki = 261 nM) and as a result, this compound is the most selective in this set (>40-fold). The 3-OH (11n) and 4-OH (11o) analogs had lower σ2 affinity (Ki = 36, 184 nM) and were less selective for σ2 over σ1 (1.6-fold, 2.5-fold) than the 2-OH analog (12m, σ2 Ki = 11 nM, σ1 Ki = 98 nM). Lastly, the 4-pyridine analog (11p) was ~8-fold less potent at σ2 (Ki = 29 nM) than the corresponding phenyl analog (11a) and less selective for σ2 over σ1 (σ1 Ki = 171 nM, 5.9-fold selectivity).
An assessment of the binding interactions that support σ2 binding of our compounds was facilitated by the availability of a crystal structure of σ2 [6]. Docking of (3) in the σ2 binding site identified in these crystal structures (Fig. 3, left) suggests that this compound forms multiple, significant interaction with the surrounding amino acids. Specifically, our analysis indicates the formation of an ionic interaction between Asp29 and the aliphatic piperazine nitrogen of (3), a π-cation interaction between Tyr147 and the same piperazine nitrogen, and a π-π interaction between Phe66 and the benzene ring of (3). Similar interactions were observed when (11a) was docked into the same model (Fig. 3 center), but in this case, the increase size of the octahydropyrrolo[3,4-c]pyrrole moiety allows the benzene ring of (11a) to form an additional π-π interaction with Tyr147. This binding interaction is not available to (3) and may explain the 10-fold increase in activity observed when the piperazine of (3) is replaced with an octahydropyrrolo[3,4-c]pyrrole in (11a).
We also assessed our compounds’ ability to inhibit the key metabolic enzymes CYP2C9, CYP2D6, and CYP3A4. Inhibition of these enzymes can lead to drug/drug interactions that create significant risks to patients [27]. All of the compounds described had little affinity for CYP2C9 (IC50 > 10,000 nM), but there was a clear SAR present with respect of CYP2D6 and CYP3A4. While none of the compounds were strong inhibitors of CYP2D6, analogs with substituents in the 2-position (11b, 11e, 11h-11j, and 11m) were notably more potent inhibitors of this enzyme (CYP2D6 IC50 = 300–1,850 nM) than the remaining analogs (CYP2D6 IC50 = 3,780 to 10,000 nM). Similarly, moderate to weak inhibition of CYP3A4 was observed (CYP3A4 IC50 = 500 to 7940 nM). In this instance, however, compounds containing a substituent in either the 2-position or 4-position where more potent CYP3A4 inhibitor than the corresponding 3-position analogs. The 2-OMe analog (11j, CYP3A4 IC50 = 2,030 nM) and 4-OMe analog (11l, CYP3A4 IC50 = 2,060), for example, were both more potent CYP3A4 inhibitors than the corresponding 3-OMe analog (11k, CYP3A4 IC50 = 7940 nM). The 2-Me analog (12e, CYP3A4 IC50 = 4,420 nM) is a notable exception to this trend, as it has CYP3A4 potency similar to that observed with the 3-Me analog (11f, CYP3A4 IC50 = 3,480 nM). while the 4-Me analog (11g, CYP3A4 IC50 = 1,530 nM) is a more potent CYP3A4 inhibitor.
Conclusion
In summary, we have demonstrated that octahydropyrrolo[3,4-c]pyrrole is a viable bioisosteric replacement for the piperazine ring in our functionalized γ-butyrolactone series of σ2 ligands. This change produces a significant increase in σ2 affinity and led to the identification of compounds with up to 40-fold σ1/σ2 selectivity (11j, σ2 Ki = 6.5 nM, σ1 Ki = 261 nM). All of the compounds examined demonstrated adequate to excellent aqueous solubility (60–200 µM), and physicochemical properties (MW, TPSA, cLogP) within drug-like space. Future studies will be focused on determining mouse liver microsomal stability of the compounds described and related analogs in an effort to identify highly potent, selective, novel σ2 binder that are suitable for in vivo pharmacokinetic and efficacy studies.
Experimental methods and materials
Reagents were purchased from Fisher Scientific, VWR International, Sigma Aldrich, and Combi-Blocks, Inc. Chromatographic purification of compounds (normal phase and reverse phase) was carried out on a Teledyne Isco Combiflash RF system. 1H-NMR and 13C spectra were obtained on a Bruker 400-MHz NMR. Chemical shift values (δ values) were reported in ppm relative to TMS. For multiplicity, s = singlet, d = doublet, t = triplet, m = multiplet. Purity (%) and mass spectral data were determined with a Waters Agilent 1200 HPLC/MS (Zorbax SB-C18, 2.1 × 30 mm, 3.5 μm, 100% water/0.1% formic acid to 100% acetonitrile/0.1% formic acid over 4.0 min, 1.0 mL/min.) with a diode array detector from 210–400 nm and Agilent 6130 quadrupole MS. All compounds were purified to 95% purity or greater as determined by HPLC/MS and 1H-NMR. Melting points were recorded on a capillary melting point apparatus.
Synthesis of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (7): To a solution of 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one (8.03 g, 43.0 mmol, 1 eq.) in tetrahydrofuran (143 mL) was added triphenylphosphine (16.94 g, 64.6 mmol, 1.5 eq.). The resulting solution was cooled to 0 °C and carbon tetrabromide (21.44 g, 64.6 mmol, 1.5 eq.) was added in one portion. The reaction was allowed to stir at 22 °C overnight. The reaction mixture was diluted with ether and filtered and concentrated onto Celite in vacuo and further purified by column chromatography (ethyl acetate/hexanes, 0–30%, solid load) (7.36 g, 69% yield). 1H NMR (400 MHz, CDCl3) δ4.60 (m, 1H), 3.53 (dd, J = 5.5, 7.6 Hz, 2H), 2.27–2.07 (m, 3H), 1.82 (dd, J = 9.3, 13.0 Hz, 1H), 1.69–1.57 (m, 4H), 0.93 (dt, J = 7.5, 25.7 Hz, 6H).
General procedure A: synthesis of tert-butyl 5-aryl-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of 2, 6- diazaspiro[3.3] heptane- 2- carboxylic acid tert- butyl ester hemioxylate (0.300 g, 1.23 mmol, 1.1 eq.) and an aryl bromide (1.12 mmol, 1.0 eq.) in anhydrous toluene (14 mL) under a nitrogen atmosphere was added the following material: Pd2(dba)3 (0.030 g, 2.5 mol %), BINAP (0.0450 g, 1.5/Pd), triethylamine (0.125 g, 1.23 mmol, 1.1 eq.) and NaOtBu (0.355 g, 3.69 mmol, 3.3 eq.). The resulting mixture was heated to 110 °C and stirred overnight under nitrogen. The reaction mixture was cooled to room temperature and then filtered through a plug of Celite. The collected filtrate was concentrated under vacuum to give a crude residue that was further purified by column chromatography (hexanes/ethyl acetate, 0–30%).
Synthesis of tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10b): The title compound was prepared according to general procedure A using 2-bromobenzonitrile (55% yield). 1H NMR (400 MHz, CDCl3) δ7.39 (dd, J = 1.6, 7.8 Hz, 1H), 7.30 (m, 1H), 6.66 (t, J = 7.5 Hz, 1H), 6.59 (d, J = 8.5 Hz, 1H), 3.80 (m, 2H), 3.61 (m, 2H), 3.52 (m, 1H), 3.44 (m, 1H), 3.28 (m, 2H), 2.95 (b, 2H), 1.42 (s, 9H); MS (LC/MS, M + H+): m/z 314.2.
Synthesis of tert-butyl 5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10c): The title compound was prepared according to general procedure A using 3-bromobenzonitrile (25% yield). 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.71-6.64 (m, 2H), 3.62 (m, 2H), 3.49 (m, 2H), 3.31 (m, 1H), 3.23 (m, 1H), 3.16 (dd, J = 3.9, 9.7 Hz, 2H), 2.99 (b, 2H), 1.42 (s, 9H); MS (LC/MS, M + H+): m/z 314.2.
Synthesis of tert-butyl 5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10d): The title compound was prepared according to general procedure A using 4-bromobenzonitrile (55% yield). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.9 Hz, 2H), 6.41 (d, J = 8.9 Hz, 2H), 3.57 (m, 2H), 3.50 (m, 2H), 3.26 (m, 1H), 3.21–3.06 (m, 3H), 2.95 (b, 2H), 1.37 (s, 9H); MS (LC/MS, M + H+): m/z 314.2.
Synthesis of tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10e): The title compound was prepared according to general procedure A using 1-bromo-2-methylbenzene (63% yield). 1H NMR (400 MHz, CDCl3) δ 7.18-7.10 (m, 2H), 6.96-6.89 (m, 2H), 3.69 (b, 2H), 3.36 (b, 2H), 3.18 (b, 2H), 3.05 (b, 2H), 2.91 (b, 2H), 2.33 (s, 3H), 1.52 (s, 9H); MS (LC/MS, M + H+): m/z 303.2
Synthesis of 2-benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole (10f): The title compound was prepared according to general procedure A using 1-bromo-2-isopropylbenzene except that the product was purified by column chromatography (dichloromethane/MeOH, 0–5%) (78% yield). 1H NMR (400 MHz, CDCl3) δ 7.54–7.33 (m, 6H), 7.32-7.11 (m, 3H), 3.77 (s, 2H), 3.65 (sept, J = 6.9 Hz, 1H), 3.15 (m, 2H), 3.09-2.99 (m, 4H), 2.96 (m, 2H), 2.47 (dd, J = 4.9, 8.8 Hz, 2H), 1.39 (d, J = 6.9 Hz, 9H); MS (LC/MS, M + H+): m/z 321.2.
Synthesis of tert-butyl 5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10g): The title compound was prepared according to general procedure A using 4-(2-bromophenyl)morpholine (83% yield). 1H NMR (400 MHz, CDCl3) δ 7.04-6.89 (m, 3H), 6.85 (d, J = 7.8 Hz, 1H), 3.85 (t, J = 4.5 Hz, 4H), 3.62 (b, 2H), 3.48–3.21 (m, 6H), 3.04 (t, J = 4.5 Hz, 4H), 2.92 (b, 2H), 1.48 (s, 9H); MS (LC/MS, M + H+): m/z 374.2.
Synthesis of tert-butyl 5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10h): The title compound was prepared according to general procedure A using 1-bromo-3-methylbenzene (76.5% yield) 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.46-6.37 (m, 2H), 3.68 (b, 2H), 3.52 (b, 2H), 3.42 (m, 1H), 3.29 (m, 1H), 3.23 (m, 2H), 2.97 (b, 2H), 2.38 (s, 3H), 1.54 (s, 9H); MS (LC/MS, M + H+): m/z 303.2.
Synthesis of tert-butyl 5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10i): The title compound was prepared according to general procedure A 1-bromo-4-methylbenzene (65.5% yield). 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.1 Hz, 2H), 6.52 (d, J = 8.5 Hz, 2H), 3.68 (m, 2H), 3.57 (b, 2H), 3.42 (m, 1H), 3.28 (m, 1H), 3.21 (m, 2H), 3.00 (b, 2H), 2.30 (s, 3H), 1.51 (s, 9H); MS (LC/MS, M + H+): m/z 303.2.
Synthesis of tert-butyl 5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10j): The title compound was prepared according to general procedure A using 1-bromo-2-methoxybenzene (78.7% yield). 1H NMR (400 MHz, CDCl3) δ 6.91–6.78 (m, 3H), 6.76–6.67 (m, 1H), 3.80 (s, 3H), 3.61 (b, 2H), 3.45 (b, 2H), 3.40-3.22 (m, 2H), 3.14 (b, 2H), 2.90 (b, 2H), 1.46 (s, 9H); MS (LC/MS, M + H+): m/z 319.2.
Synthesis of tert-butyl 5-(3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10k): The title compound was prepared according to general procedure A using 1-bromo-3-methoxybenzene (64% yield). 1H NMR (400 MHz, CDCl3) δ 7.13 (t, J = 8.1 Hz, 1H), 6.29 (dd, J = 2.2, 8.1 Hz, 1H), 6.18 (dd, J = 1.8, 8.1 Hz, 1H), 6.10 (t, J = 2.2 Hz, 1H), 3.79 (s, 3H), 3.63 (m, 2H), 3.50 (m, 2H), 3.37 (m, 1H), 3.30–3.11 (m, 3H), 2.95 (b, 2H), 1.48 (s, 9H); MS (LC/MS, M + H+): m/z 319.2.
Synthesis of tert-butyl 5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10l): The title compound was prepared according to general procedure A using 1-bromo-4-methoxybenzene (66% yield). 1H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 9.0 Hz, 2H), 6.50 (d, J = 9.0 Hz, 2H), 3.73 (s, 3H), 3.62 (m, 2H), 3.48-3.29 (m, 3H), 3.23 (m, 1H), 3.12 (dd, J = 3.5, 9.3 Hz, 2H), 2.93 (b, 2H), 1.46 (s, 9H); MS (LC/MS, M + H+): m/z 319.2.
Synthesis of tert-butyl 5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The title compound was prepared according to general procedure A using 1-(benzyloxy)-2-bromobenzene (82% yield) 1H NMR (400 MHz, CDCl3) δ 7.36–7.23 (m, 4H), 7.20 (m, 1H), 6.79 (m, 2H), 6.72 (m, 1H), 6.65 (m, 1H), 4.94 (s, 2H), 3.50 (b, 2H), 3.33 (m, 2H), 3.27–3.02 (m, 3H), 2.76 (b, 2H), 1.35 (s, 9H); MS (LC/MS, M + H+): m/z 395.2.
Synthesis of tert-butyl 5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The title compound was prepared according to general procedure A using 1-(benzyloxy)-3-bromobenzene (66% yield). 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.34 (m, 1H), 7.17 (t, J = 8.2 Hz, 1H), 6.39 (dd, J = 1.7, 8.0 Hz, 1H), 6.23 (m, 2H), 5.08 (s, 2H), 3.66 (m, 2H), 3.53 (m, 2H), 3.40 (m, 1H), 3.33–3.14 (m, 3H), 2.99 (b, 2H), 1.49 (s, 9H); MS (LC/MS, M + H+): m/z 395.2.
Synthesis of tert-butyl 5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: The title compound was prepared according to general procedure A 1-(benzyloxy)-4-bromobenzene (55% yield). 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.34 (m, 1H), 6.95 (d, J = 9.0 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 5.03 (s, 2H), 3.67 (b, 2H), 3.47 (b, 2H), 3.40 (m, 1H), 3.28 (m, 1H), 3.18 (dd, J = 3.4, 9.3 Hz, 2H), 2.99 (b, 2H), 1.50 (s, 9H); MS (LC/MS, M + H+): m/z 395.2.
General procedure B: Synthesis of 1-(benzyloxy)-2-bromobenzene: To a solution of 2-bromophenol (1.0 g, 5.78 mmol, 1.01 eq.) in acetonitrile (14 mL) was added benzyl bromide (0.975 g, 5.7 mmol, 1.0 eq.) and K2CO3 (1.09 g, 7.87 mmol, 1.38 eq.). This mixture was allowed to stir at 22 °C overnight. The reaction was filtered and concentrated under vacuum to give a crude residue that was further purified by column chromatography (hexanes/ethyl acetate, 0–10%) (95% yield). 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 1.6, 7.8 Hz, 1H), 7.51 (m, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.35 (m, 1H), 7.29–7.22 (m, 1H), 6.97 (dd, J = 1.2 8.3 Hz, 1H), 6.88 (td, J = 1.3, 7.6 Hz, 1H), 5.19 (s, 2H).
Synthesis of 1-(benzyloxy)-3-bromobenzene: The title compound was prepared according to general procedure B using 3-bromophenol (93% yield). 1H NMR (400 MHz, CDCl3) δ 7.50–7.34 (m, 5H), 7.23–7.10 (m, 3H), 6.95 (m, 1H), 5.08 (s, 2H).
Synthesis of 1-(benzyloxy)-4-bromobenzene: The title compound was prepared according to general procedure B using 4-bromophenol (94% yield). 1H NMR (400 MHz, CDCl3) δ 7.51–7.33 (m, 7H), 6.91 (d, J = 9.1 Hz, 2H), 5.08 (s, 2H).
General procedure C: Synthesis of 3,3-diethyl-5-aryl-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-ones: To a solution of tert-butyl 5-aryl-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.62 mmol, 1 eq.) in methylene chloride (4 mL) at 0 °C was added trifluoroacetic acid (2 mL). The reaction was allowed to stir at 22 °C for 30 minutes before being diluted with MeOH and concentrated under vacuum to afford the product as a TFA salt. The salt was then suspended in sat. NaHCO3 solution and the free based product was extracted with methylene chloride (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentration in vacuo to afford 2-aryl-octahydropyrrolo[3,4-c]pyrrole as a free base which was used without further purification.
Next, a mixture of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (7) (0.075 g, 0.301 mmol, 1 eq.), acetonitrile (3 mL), the 2-arl-octahydropyrrolo[3,4-c]pyrrole (0.361 mmol, 1.2 eq.) and N,N-diisopropylethyl amine (0.116 g, 0.903 mmol, 3 eq.) was microwaved at 120 °C for 4 h. The resulting solution was concentrated under vacuum to give a crude residue that was purified by column chromatography (methanol/dichloromethane, 0–10%) to provide the 3,3-diethyl-5-aryl-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one.
General procedure D: Synthesis of 3,3-diethyl-5-aryl-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-ones: To a solution of tert-butyl 5-aryl-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.62 mmol, 1 eq.) in MeOH (1.25 mL) at 0 °C was added 1 M methanolic HCl (3.75 mL). The reaction was allowed to stir at 22 °C overnight before being diluted with MeOH and concentrated under vacuum to afford the product as a HCl salt which was used without further purification.
Next, a mixture of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (7) (0.075 g, 0.301 mmol, 1 eq.), acetonitrile (3 mL), the 2-arl-octahydropyrrolo[3,4-c]pyrrole (0.361 mmol, 1.2 eq.) and N,N-diisopropylethyl amine (0.116 g, 0.903 mmol, 3 eq.) was microwaved at 120 °C for 4 h. The resulting solution was concentrated under vacuum to give a crude residue that was purified by column chromatography (methanol/dichloromethane, 0–10%) to provide the 3,3-diethyl-5-aryl-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one.
Synthesis of 3,3-diethyl-5-(2-(5-phenylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11a): The title compound was prepared according to general procedure C except 2-phenyloctahydropyrrolo[3,4-c]pyrrole was acquired from a commercial source rather than prepared from the Boc-protected analog (58% yield, HPLC purity: 98.2%). 1H NMR (400 MHz, CDCl3) δ 7.14 (m, 2H), 6.64 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.5 Hz, 2H), 4.37 (m, 1H), 3.29 (t, J = 8.1 Hz, 2H), 3.08 (dt, J = 2.7, 9.3 Hz, 2H), 2.92–2.79 (b, 2H), 2.78–2.65 (m, 2H), 2.47 (t, J = 6.9 Hz, 2H), 2.32 (dd, J = 4.0, 8.9 Hz, 2H), 2.02 (dd, J = 6.7, 13.1 Hz, 1H), 1.87–1.61 (m, 3H), 1.51 (q, J = 7.3 Hz, 4H), 0.81 (dt, J = 7.5, 13.9 Hz, 6H); 13C NMR (101 MHz, DMSO-d6) δ 179.9, 148.5, 128.8, 116.4, 113.4, 75.3, 60.1, 54.2, 50.8, 47.7, 40.8, 36.7, 34.3, 28.2, 27.5, 8.5, 8.4. MS (LC/MS, M + H+): m/z 357.2.
Synthesis of 2-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile (11b): The title compound was prepared according to general procedure D using tert-butyl 5-(2-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50% yield, HPLC purity: 99.5%). 1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 1.5, 7.6 Hz, 1H), 7.36 (m, 1H), 6.81–6.68 (m, 2H), 4.45 (m, 1H), 3.62 (m, 2H), 3.45 (td, J = 2.0, 8.6 Hz, 2H), 2.92 (b, 2H), 2.74 (m, 2H), 2.63–2.53 (m, 2H), 2.52–2.46 (m, 2H), 2.11 (dd, J = 6.8, 13.0 Hz, 1H), 1.94–1.70 (m, 3H), 1.58 (qd, J = 2.6, 7.4 Hz, 4H), 0.88 (dt, J = 7.3, 14.8 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 177.9, 148.2, 133.0, 131.9, 118.2, 116.2, 114.7, 95.2, 72.9, 57.0, 52.9, 48.5, 45.7, 38.5, 36.8, 34.6, 26.2, 25.5, 6.4, 6.3. MS (LC/MS, M + H+): m/z 382.2.
Synthesis of 3-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile (11c): The title compound was prepared according to general procedure D using tert-butyl 5-(3-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (57% yield, HPLC purity: 98.9%). 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.82–6.75 (m, 2H), 4.44 (m, 1H), 3.44 (t, J = 8.7 Hz, 2H), 3.15 (dt, J = 3.8, 9.4 Hz, 2H), 2.98 (b, 2H), 2.73 (m, 2H), 2.57 (t, J = 7.0 Hz, 2H), 2.50 (dd, J = 3.1, 9.1 Hz, 2H), 2.10 (dd, J = 6.8, 12.9 Hz, 1H), 1.94–1.70 (m, 3H), 1.59 (q, J = 7.3 Hz, 4H), 0.89 (dt, J = 5.4, 14.9 Hz, 6H), 13C NMR (101 MHz, DMSO-d6) δ 179.9, 148.2, 130.0, 119.4, 119.2, 117.7, 115.5, 111.7, 75.2, 60.0, 54.1, 50.6, 47.8, 40.8, 36.7, 34.1, 28.2, 27.6, 8.5, 8.4. MS (LC/MS, M + H+): m/z 382.2.
Synthesis of 4-(5-(2-(4,4-diethyl-5-oxotetrahydrofuran-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzonitrile (11d): The title compound was prepared according to general procedure C using tert-butyl 5-(4-cyanophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (37% yield, HPLC purity: 99.1%). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.9 Hz, 2H), 6.54 (d, J = 8.7 Hz, 2H), 4.44 (m, 1H), 3.55 (t, J = 9.0 Hz, 2H), 3.23 (dt, J = 3.6, 9.9 Hz, 2H), 3.00 (b, 2H), 2.72 (m, 2H), 2.64–2.50 (m, 4H), 2.10 (dd, J = 6.7, 13.1 Hz, 1H), 1.94–1.71 (m, 3H), 1.59 (q, J = 7.5 Hz, 4H), 0.89 (dt, J = 5.1, 14.9 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 179.9, 150.2, 133.2, 120.5, 112.8, 112.6, 75.4, 59.8, 55.1, 50.6, 47.8, 40.6, 36.6, 34.5, 28.1, 27.6, 8.6, 8.4. MS (LC/MS, M + H+): m/z 382.2.
Synthesis of 3,3-diethyl-5-(2-(5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11e): The title compound was prepared according to general procedure C using tert-butyl 5-(o-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (62% yield, HPLC purity: 99.2%). 1H NMR (400 MHz, CDCl3) δ 7.15 (m, 2H), 6.96 (m, 2H), 4.50 (m, 1H), 3.08-2.92 (m, 6H), 2.86 (b, 2H), 2.60 (t, J = 6.9 Hz, 2H), 2.37–2.24 (m, 5H), 2.14 (dd, J = 6.7, 13.0 Hz, 1H), 1.99–1.75 (m, 3H), 1.64 (m, 4H), 0.94 (dt, J = 7.4, 18.1 Hz, 6H), 13C NMR (101 MHz, DMSO-d6) δ 179.9, 147.6, 130.9, 130.6, 126.4, 122.0, 117.7, 74.9, 59.1, 55.5, 50.5, 47.8, 40.5, 36.6, 34.5, 28.2, 27.5, 18.8, 8.5, 8.4. MS (LC/MS, M + H+): m/z 371.2.
Synthesis of 3,3-diethyl-5-(2-(5-(2-morpholinophenyl)hexahydropyrrolo [3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11g): The title compound was prepared according to general procedure D using tert-butyl 5-(2-morpholinophenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (52% yield, HPLC purity: 98.9%). 1H NMR (400 MHz, CDCl3) δ 7.05–6.94 (m, 3H), 6.91-6.83 (m, 1H), 4.49 (m, 1H) 3.85 (t, J = 4.7 Hz, 4H), 3.68-3.42 (m, 4H), 3.22–2.84 (m, 10H), 2.61 (b, 2H), 2.30 (b, 1H), 2.19 (dd, J = 6.7, 13.2 Hz, 1H), 2.05–1.90 (m, 1H), 1.84 (dd, J = 9.3, 13.2 Hz, 1H), 1.67–1.56 (m, 4H), 0.91 (dt, J = 7.3, 16.5 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 179.8, 143,2, 141.8, 122.9, 121.7, 118.3, 117.7, 74.5, 66.5, 58.8, 53.2, 50.3, 49.9, 48.5, 47.8, 40.1, 36.5, 28.2, 27.6, 8.5, 8.4. MS (LC/MS, M + H+): m/z 442.2.
Synthesis of 3,3-diethyl-5-(2-(5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11h): The title compound was prepared according to general procedure C using tert-butyl 5-(m-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (46% yield, HPLC purity: 98.7%). 1H NMR (400 MHz, CDCl3) δ 7.13 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 6.53–6.45 (m, 2H), 4.47 (m, 1H), 3.37 (m, 2H), 3.18 (dt, J = 2.8, 9.4 Hz, 2H), 2.95 (b, 2H), 2.86 (m, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.41 (dd, J = 4.0, 8.9 Hz, 2H), 2.33 (s, 3H), 2.12 (dd, J = 6.6, 13.0 Hz, 1H), 1.97–1.73 (m, 3H), 1.62 (q, J = 7.5 Hz, 4H), 0.92 (dt, J = 7.5, 14.8 Hz, 6H), 13C NMR (101 MHz, DMSO-d6) δ 178.6, 147.2, 136.4, 127.3, 116.0, 112.8, 109.4, 73.9, 58.8, 52.9, 49.4, 46.4, 39.5, 35.4, 34.3, 26.9, 26.2, 20.1, 7.1, 7.0. MS (LC/MS, M + H+): m/z 371.2.
Synthesis of 3,3-diethyl-5-(2-(5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl) dihydrofuran-2(3H)-one (11i): The title compound was prepared according to general procedure C using tert-butyl 5-(p-tolyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (43% yield, HPLC purity: 99.5%). 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 8.4 Hz, 2H), 4.32 (m, 1H), 3.17 (m, 2H), 2.99 (dt, J = 3.0, 9.2 Hz, 2H), 2.78 (b, 2H), 2.70 (m, 2H), 2.42 (t, J = 6.9 Hz, 2H), 2.42 (dd, J = 4.0, 8.8 Hz, 2H), 2.11 (s, 3H), 2.97 (dd, J = 6.8, 13.0 Hz, 1H), 1.81–1.57 (m, 3H), 1.45 (q, J = 7.2 Hz, 4H), 0.76 (dt, J = 7.5, 14.7 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 179.9, 146.6, 129.3, 125.2, 113.8, 75.1, 59.8, 54.2, 50.6, 47.8, 40.7, 36.7, 34.9, 28.2, 27.5, 20.0, 8.5, 8.4. MS (LC/MS, M + H+): m/z 371.2.
Synthesis of 3,3-diethyl-5-(2-(5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11j): The title compound was prepared according to general procedure C using 2-(2-methoxyphenyl)octahydropyrrolo[3,4-c]pyrrole (65% yield, HPLC purity: 98.9%). 1H NMR (400 MHz, CDCl3) δ 6.83–6.61 (m, 4H), 4.34 (m, 1H), 3.71 (s, 3H), 3.23 (q, J = 7.5 Hz, 2H), 2.86 (m, 2H), 2.72 (b, 2H), 2.58 (b, 2H), 2.44 (m, 2H), 2.31 (dt, J = 3.2, 8.8 Hz, 2H), 1.98 (dd, J = 6.8, 13.1 Hz, 1H), 1.84-1.73 (m, 1H), 1.73–1.58 (m, 2H), 1.47 (qd, J = 1.5, 7.5 Hz, 4H), 0.77 (dt, J = 7.3, 15.8 Hz, 6H), 13C NMR (101 MHz, DMSO) δ 179.9, 150.9, 138.7, 120.9, 120.7, 116.7, 111.9, 75.2, 59.4, 55.4, 55.3, 50.7, 47.8, 40.6, 36.7, 34.7, 28.2, 27.6, 8.5, 8.4. MS (LC/MS, M + H+): m/z 387.2.
Synthesis of 3,3-diethyl-5-(2-(5-(3-methoxyphenyl)hexahydropyrrolo [3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11k): The title compound was prepared according to general procedure C using tert-butyl 5-(2-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (53% yield, HPLC purity: 99.7%). 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J = 8.2 Hz, 1H), 6.30 (m, 2H), 6.20 (t, J = 2.2 Hz, 1H), 4.46 (m, 1H), 3.79 (s, 3H), 3.38 (t, J = 8.2 Hz, 2H), 3.17 (dt, J = 3.0, 9.5 Hz, 2H), 2.94 (b, 2H), 2.86–2.77 (m, 2H), 2.57 (t, J = 7.1 Hz, 2H), 2.42 (dd, J = 3.9, 9.0 Hz, 2H), 2.11 (dd, J = 6.8, 13.0 Hz, 1H), 1.95–1.72 (m, 3H), 1.61 (qd, J = 1.5, 7.5 Hz, 4H), 0.91 (dt, J = 7.4, 14.8 Hz, 6H); DMSO-d6, DMSO) δ 179.9, 160.1, 149.7, 129.5, 106.3, 101.9, 99.3, 75.3, 60.2, 54.7, 54.4, 50.8, 47.8, 40.8, 36.7, 34.4, 28.2, 27.5, 8.5, 8.4. MS (LC/MS, M + H+): m/z 387.2.
Synthesis of 3,3-diethyl-5-(2-(5-(4-methoxyphenyl)hexahydropyrrolo [3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11l): The title compound was prepared according to general procedure C using tert-butyl 5-(4-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (52% yield, HPLC purity: 99.3%). 1H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 9.0 Hz, 2H), 6.65 (d, J = 9.0 Hz, 2H), 4.46 (m, 1H), 3.76 (s, 3H), 3.28 (m, 2H), 3.10 (dt, J = 3.2, 9.1 Hz, 2H), 2.92 (b, 2H), 2.84 (b, 2H), 2.63-2.51 (m, 2H), 2.39 (dd, J = 4.0, 8.7 Hz, 2H), 2.11 (dd, J = 6.8, 13.0 Hz, 1H), 1.97–1.71 (m, 3H), 1.61 (qd, J = 1.3, 7.4 Hz, 4H), 0.91 (dt, J = 7.3, 14.8 Hz, 6H), 13C NMR (101 MHz, DMSO-d6) δ 179.9, 151.3, 143.4, 114.8, 114.4, 75.3, 60.2, 55.2, 55.1, 50.8, 47.8, 41.0, 36.7, 34.5, 28.2, 27.5, 8.5, 8.4. MS (LC/MS, M + H+): m/z 387.2.
Synthesis of 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one: The title compound was prepared according to general procedure D using tert-butyl 5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (43% yield). 1H NMR (400 MHz, CDCl3) δ 7.46–7.29 (m, 5H), 7.01–6.86 (m, 3H), 6.81 (dd, J = 1.4, 7.7 Hz, 1H), 5.03 (s, 2H), 4.43 (m, 1H), 3.61 (b, 2H), 3.36 (t, J = 10.6 Hz, 2H), 3.17–2.97 (m, 3H), 2.91 (td, J = 5.3, 12.2 Hz, 1H), 2.86–2.73 (m, 2H), 2.58–2.37 (m, 2H), 2.30 (m, 1H), 2.17 (dd, J = 6.7, 13.1 Hz, 1H), 1.92–1.73 (m, 2H), 1.61 (q, J = 7.4 Hz, 4H), 0.91 (dt, J = 7.0, 13.9 Hz, 6H), MS (LC/MS, M + H+): m/z 463.2.
Synthesis of 5-(2-(5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one: The title compound was prepared according to general procedure D using tert-butyl 5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (39% yield). 1H NMR (400 MHz, CDCl3) δ 7.39–7.33 (m, 2H), 7.33–7.26 (m, 2H), 7.26–7.20 (m, 1H), 7.05 (m, 1H), 6.29 (dd, J = 1.7, 8.1 Hz, 1H), 6.24–6.18 (m, 2H), 4.96 (s, 2H), 4.37 (m, 1H), 3.28 (m, 2H), 3.08 (dt, J = 2.9, 9.3 Hz, 2H), 2.93–2.81 (m, 2H), 2.81–2.69 (m, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.33 (dd, J 3.9, 8.9 Hz, 2H), 2.02 (dd, J = 6.7, 13.0 Hz, 1H), 1.87–1.63 (m, 3H), 1.52 (qd, J = 1.2, 7.4 Hz, 4H), 0.82 (dt, J = 7.4, 14.9 Hz, 6H). MS (LC/MS, M + H+): m/z 463.2.
Synthesis of 5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one: The title compound was prepared according to general procedure D using tert-butyl 5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50% yield). 1H NMR (400 MHz, CDCl3) δ 7.37-7.31 (m, 2H), 7.31–7.25 (m, 2H), 7.24–7.18 (m, 1H), 6.81 (d, J = 9.0 Hz, 2H), 6.55 (d, J = 9.0 Hz, 2H), 4.92 (s, 2H), 4.37 (m, 1H), 3.19 (m, 2H), 3.01 (dt, J = 3.1, 9.3 Hz, 2H), 2.89–2.80 (m, 2H), 2.80–2.70 (m, 2H), 2.48 (t, J = 6.9 Hz, 2H), 2.29 (dd, J 3.9, 8.6 Hz, 2H), 2.02 (dd, J = 6.7, 13.1 Hz, 1H), 1.87–1.62 (m, 3H), 1.52 (q, J = 7.3 Hz, 4H), 0.82 (dt, J = 7.5, 14.5 Hz, 6H). MS (LC/MS, M + H+): m/z 463.2.
Synthesis of 3,3-diethyl-5-(2-(5-(2-isopropylphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11f): To a dry round bottom flask, 0.04 g of 10% Pd/C (20% wt) was added and wet with a small amount of ethyl acetate. Following, a solution of 2-benzyl-5-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole (0.20 g, 0.624 mmol, 1 eq.) in MeOH (2.1 mL) was added slowly to the Pd/C containing round bottom flask. This system was then flushed 3x with H2, using a balloon filled with H2. The reaction was allowed to stir under 1 atm H2 for five days at room temperature. The Pd/C was removed via filtration through a plug of Celite. The filtrate was concentrated under vacuum to afford a crude oil of 2-(2-isopropylphenyl)octahydropyrrolo[3,4-c]pyrrole which was used in the next step without further purification. The second step of the sequence was then performed according to general procedure (A) (52% yield, HPLC purity: 99.1%). (1H NMR (400 MHz, CDCl3) δ 7.18 (dd, J = 1.5, 7.4 Hz, 1H), 7.10–6.90 (m, 3H), 4.43 (m, 1H), 3.38 (sept, J = 6.9 Hz, 1H), 3.01–2.84 (m, 4H), 2.83–2.66 (m, 4H), 2.52 (t, J = 6.8 Hz, 2H), 2.19 (m, 2H), 2.06 (dd, J = 6.8, 13.1 Hz, 1H), 1.91–1.67 (m, 3H), 1.63-1.44 (m, 4H), 1.15 (d, J = 6.9 Hz, 6H), 0.86 (dt, J = 7.3, 19.3 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 180.0, 146.7, 143.4, 126.1, 126.0, 123.5, 119.2, 75.3, 59.6, 58.2, 51.0, 47.8, 41.3, 36.8, 34.5, 28.3, 27.6, 26.4, 23.9, 8.5, 8.4. MS (LC/MS, M + H+): m/z 399.2.
General Procedure E: Synthesis of 3,3-diethyl-5-(2-(5-(2-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11m): To a dry round bottom flask, 0.013 g of 10% Pd/C (20% wt) was added and wet with a small amount of ethyl acetate. Following, a solution of 5-(2-(5-(2-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one (0.065 g, 0.140 mmol, 1 eq.) in MeOH (1.5 mL) was added slowly to the Pd/C containing round bottom flask. This system was then flushed 3x with H2, using a balloon filled with H2. The reaction was allowed to stir under 1 atm H2 for overnight at room temperature. The Pd/C was removed via filtration through a plug of Celite. The filtrate was concentrated under vacuum to give a crude residue that was first purified by column chromatography (methanol/dichloromethane, 0–10%) (86% yield, HPLC purity: 99.4%). 1H NMR (400 MHz, CDCl3) δ 7.13 (dd, J = 1.3, 7.8 Hz, 1H), 7.05 (td, J = 1.3, 7.7 Hz, 1H), 6.93 (dd, J = 1.3, 8.1 Hz, 1H), 6.85 (td, J = 1.4, 7.7 Hz, 1H), 4.52 (m, 1H), 3.12–3.00 (m, 2H), 2.98–2.74 (m, 6H), 2.65 (t, J = 7.3 Hz, 2H), 2.58–2.46 (m, 2H), 2.16 (dd, J = 6.7, 13.1 Hz, 1H), 2.00–1.76 (m, 3H), 1.64 (q, J = 7.5 Hz, 4H), 0.95 (dt, J = 7.4, 22.8 Hz, 6H), 13C NMR (101 MHz, DMSO-d6) δ 179.6, 147.4, 136.0, 119.4, 117.8, 115.8, 113.9, 73.8, 58.1, 53.9, 49.3, 46.4, 39.3, 35.3, 32.9, 26.8, 26.2, 7.1, 7.0. MS (LC/MS, M + H+): m/z 373.2.
Synthesis of 3,3-diethyl-5-(2-(5-(3-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11n): The title compound was prepared according to general procedure E using 5-(2-(5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydro furan-2(3H)-one (88% yield, HPLC purity: 99.7%). 1H NMR (400 MHz, CDCl3) δ 6.85 (t, J = 8.1 Hz, 1H), 6.00 (td, J = 1.8, 7.6 Hz, 2H), 5.91 (t, J = 2.3 Hz, 1H), 4.24 (m, 1H), 3.18-3.05 (m, 2H), 2.97 (d, J = 9.2 Hz, 2H), 2.83–2.64 (m, 4H), 2.44 (t, J = 7.3 Hz, 2H), 2.25 (m, 2H), 1.91 (dd, J = 6.7, 13.1 Hz, 1H), 1.77–1.53 (m, 3H), 1.40 (q, J = 7.4 Hz, 4H), 0.70 (dt, J = 7.4, 15.6 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 179.9, 157.9. 149.8, 129.4, 104.8, 104.0, 100.5, 75.3, 60.2, 54.3, 50.8, 47.8, 40.8, 36.7, 34.2, 28.2, 27.5, 8.5, 8.4. MS (LC/MS, M + H+): m/z 373.2.
Synthesis of 3,3-diethyl-5-(2-(5-(4-hydroxyphenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one trifluoroacetate (11o): The title compound was prepared according to general procedure E using 5-(2-(5-(4-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one and the reaction time was extended to 3 days. A second purification was also conducted via column chromatography on a C18 column. (acetonitrile /H2O, 0–100%, w/ 0.1% TFA) (93% yield, HPLC purity: 98.9%). 1H NMR (400 MHz, MeOD) δ 6.78-6.67 (m, 4H), 4.54 (m, 1H), 3.69 (b, 2H), 3.45 (dd, J = 7.2, 9.6 Hz, 2H), 3.40–3.09 (m, 6H), 2.98 (m, 2H), 2.28 (dd, J = 6.7, 13.2 Hz, 1H), 2.20–1.97 (m, 2H), 1.91 (dd, J = 9.4, 13.2 Hz, 1H), 1.74–1.52 (m, 4H), 0.94 (dt, J = 5.0, 14.9 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 179.7, 149.7, 141.7, 115.7, 115.5, 74.2, 58.9, 54.7, 50.6, 47.8, 40.1, 36.4, 31.9, 28.2, 27.5, 8.4, 8.3., MS (LC/MS, M + H+): m/z 373.2.
Synthesis of 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydro furan-2(3H)-one (15): A solution of 5-(2-bromoethyl)-3,3-diethyldihydrofuran-2(3H)-one (0.400 g, 1.53 mmol, 1 eq.), acetonitrile (8 mL), 2-benzyloctahydropyrrolo[3,4-c]pyrrole (0.340 g, 1.68 mmol, 1.1 eq.) and K2CO3 (1.05 g, 7.65 mmol, 5 eq.) was heated and stirred at 80 °C for 24 hours. The resulting mixture was then filtered and concentrated under vacuum to give a crude residue that was further purified by column chromatography (methanol/dichloromethane, 0–10%) (51% yield). 1H NMR (400 MHz, CDCl3) δ 7.25–7.14 (m, 4H), 7.14–7.06 (m, 1H), 4.38 (m, 1H), 3.46 (s, 2H), 2.64–2.48 (m, 6H), 2.48–2.38 (m, 2H), 2.28–2.13 (m, 4H), 2.02 (dd, J = 6.8, 13.0 Hz, 1H), 1.87–1.59 (m, 3H), 1.58–1.44 (m, 4H), 0.83 (dt, J = 7.3, 21.4 Hz, 6H); MS (LC/MS, M + H+): m/z 371.2.
Synthesis of 3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one: A mixture of 5-(2-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-3,3-diethyldihydrofuran-2(3H)-one (540 mg, 1.46 mmol, 1 eq.), Pd/C (108 mg, 20% wt) and MeOH (5.0 mL) was stirred at 22 °C under 1 atm of H2 (filled balloon) for three days. The mixture was filtered through a plug of Celite, washed with MeOH (50 mL) and concentrated under vacuum to give a crude product that was used in following steps without further purification (87% yield). 1H NMR (400 MHz, CDCl3) δ 4.42 (m, 1H), 2.83 (b, 1H), 2.69 (m, 2H), 2.55-2.39 (m, 4H), 2.33 (m, 2H), 2.26 (t, J = 7.0 Hz, 2H), 2.14 (dd, J = 1.7, 9.0 Hz, 2H), 1.91 (dd, J = 6.7, 13.0 Hz, 1H), 1.71–1.47 (m, 3H), 1.45–1.32 (m, 4H), 0.69 (dt, J = 7.4, 19.2 Hz, 6H); MS (LC/MS, M + H+): m/z 281.2
Synthesis of 3,3-diethyl-5-(2-(5-(pyridin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (11p): A solution of 3,3-diethyl-5-(2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)dihydrofuran-2(3H)-one (0.180 g, 0.642 mmol, 1 eq.), 1-butanol (6.4 mL), 4-bromopyridine hydrochloride (0.249 g, 1.28 mmol, 2.0 eq.) and triethylamine (0.325 g, 3.21 mmol, 5 eq.) was heated and stirred at 120 °C for 24 h. The resulting solution was concentrated under vacuum to give a crude residue that was further purified by column chromatography (methanol/dichloromethane, 0–10%, w/ 0.1% NH4OH) (66% yield, HPLC purity: 99.2%). 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 1.4, 3.5 Hz, 2H), 6.32 (dd, J = 1.5, 3.5 Hz, 2H), 4.37 (m, 1H), 3.45 (dd, J = 8.3, 9.2 Hz, 2H), 3.12 (dt, J = 3.4, 9.9 Hz, 2H), 2.90 (m, 2H), 2.62 (m, 2H), 2.50 (t, J = 7.4 Hz, 2H), 2.46 (m, 2H), 2.02 (dd, J = 6.8, 13.0 Hz, 1H), 1.85-1.61 (m, 3H), 1.52 (q, J = 7.5 Hz, 4H), 0.82 (dt, J = 5.7, 13.2 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 179.7, 152.3, 149.7, 110.2, 74.9, 60.3, 54.7, 50.9, 47.4, 40.9, 36.8, 34.5, 28.3, 27.7, 8.5, 8.4. MS (LC/MS, M + H+): m/z 358.2
Computational values and docking studies
TPSA and cLogP values were calculated using the Dotmatics software suite (Dotmatics LLC The Old Monastery, Windhill Bishops, Stortford Herts, CW23 2ND UK). Docking studies and analysis were conducted using Schrodinger’s Glide and Pymol software packages (Schrodinger Inc.1540 Broadway, 24th Floor, New York, NY 10036). Briefly, the crystal structure of sigma-2 receptor bound to a dihydroquinolinone derivative was obtained from the protein data bank (PDD ID: 7M96). The protein structure was prepared by adding missing atoms, adjusting the bond orders, filling in missing side chains and completing missing loops [29,30,31,32,33]. Water molecules beyond 4A of the ligand were deleted. The tautomerization and protonation states of the amino acids at pH of 7.4 were enumerated to adjust the hydrogen bonding network. Then, the protein structure was minimized using OPLSe force-field and charges. The receptor grid was generated by using Glide [34,35,36,37]. The center of the grid was defined based on the bound ligand coordinates. A van der Waals scaling factor of 0.8 was used to add some flexibility during the docking step. The ligands were prepared for docking by LigPrep [38]. The docking was carried out by Glide standard precision algorithm.
Sigma-1 and sigma-2 competitive radioligand-binding studies
Competitive binding assays were conducted by the Psychoactive Drug Screening Program (PDSP) at The University of North Carolina, Chapel Hill under the direction of Professor Bryan Roth [28]. Assay conditions can be found in the PDSP assay protocol book at https://pdsp.unc.edu/pdspweb/content/UNC-CH%20Protocol%20Book.pdf.
Aqueous solubility assay
Compounds were assessed for their solubility at pH 7.4 using the commercially available Millipore MultiScreenTM Solubility filter system (Millipore, Billerica, MA). Analysis was performed by liquid chromatography tandem mass spectrometry (LC/MS/MS).
Cytochrome P450 inhibition assay
Compounds were assessed for their ability to inhibit human cytochrome P450 3A4 using testosterone as a substrate and LC/MS/MS analysis, while the 2D6 and 2C9 assays use fluorescent substrates and Envision plate reader analysis. Expressed enzymes was used to minimize non-specific binding and membrane partitioning issues [39].
References
Martin WR, Eades CE, Thompson JA, Huppler RE. The effects of morphine and nalorphine-like drugs in the non-dependent and morphine-dependent chronic spinal dog. J Pharm Exp Ther. 1976;197:517–32.
Su TP. Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther. 1982;223:284–90. https://doi.org/10.1007/s00044-020-02574-9
Khazan N, Young GA, El-Fakany EE, Hong O, Caliigaro D. Sigma receptors mediated the psychotomimetic effects of N-allylnormetazocine (SKF-10,047), but not its opioid agonistic-antagonistic properties. Neuropharmacology. 1984;23:983–7. https://doi.org/10.1016/0028-3908(84)90015-7
Bowen WD, de Costa BR, Hellewell SB, Walker JM, Rice KC. [3H]-(+)-Pentazocine: a potent and highly selective benzomorphan-based probe for sigma-1 receptors. Mol Neuropharmacol. 1993;3:117–26.
Schmidt HR, Zheng S, Guripinar E, Koehl A, Manglik A, Kruse AC. Crystal structure of the human σ1 receptor. Nature 2016;532:527–30. https://doi.org/10.1038/nature17391. 28
Alon A, Lyu J, Braz JM, Tummino TA, Craik V, O’Meara MJ, et al. Structures of the σ2 receptor enable docking for bioactive ligand discovery. Nature. 2021;600:759–64. https://doi.org/10.1038/s41586-021-04175-x
Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Krusea AC. Identification of the gene that codes for the σ2. receptor, Proc Natl Acad Sci USA 2017;114:7160–5. https://doi.org/10.1073/pnas.1705154114
Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T, et al. Identification of cholesterol-regulating genes by targeted RNAi screening. Cell Metab. 2009;10:63–75. https://doi.org/10.1016/j.cmet.2009.05.009
Ebrahimi-Fakhar D, Wahlster L, Bartz F, Werenbeck-Ueding J, Praggastis M, Zhang J, et al. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells. Hum Mol Genet. 2016;25:3588–99. https://doi.org/10.1093/hmg/ddw204. 15
Guo L, Zhen X. Sigma-2 receptor ligands: neurobiological effects. Curr Med Chem 2015;22:989–1003. https://doi.org/10.2174/0929867322666150114163607
Intagliata S, Sharma A, King TI, Mesangeau C, Seminerio M, Chin FT, et al. Discovery of a highly selective sigma-2 receptor ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with drug-like properties and antinociceptive effects in vivo. AAPS J. 2020;22:94 https://doi.org/10.1208/s12248-020-00472-x
Sahn JJ, Mejia GL, Ray PR, Martin SF, Price TJ. Sigma 2 receptor/Tmem97 agonists produce long lasting antineuropathic pain effects in mice. ACS Chem Neurosci. 2017;8:1801–11. https://doi.org/10.1021/acschemneuro.7b00200
Vazquez-Rosa E, Watson MR, Sahn JJ, Hodges TR, Schroeder RE, Cintron-Perez CJ, et al. Neuroprotective efficacy of a sigma 2 receptor/TMEM97 modulator (DKR-1677) after traumatic brain injury. ACS Chem Neurosci. 2019;10:1595–602. https://doi.org/10.1021/acschemneuro.8b00543
Abatematteo FS, Niso M, Lacivita E, Abate C. σ2 Receptor and its role in cancer with focus on a multitarget directed ligand (MTDL) approach. Molecules 2021;26:3743 https://doi.org/10.3390/molecules26123743.
Asong G, Zhu XY, Bricker B, Andey T, Amissah F, Lamango N, et al. New analogs of SYA013 as sigma-2 ligands with anticancer activity. Bioorg Med Chem. 2019;27:2629–36. https://doi.org/10.1016/j.bmc.2019.04.012
Intagliata S, Alsharif WF, Mesangeau C, Fazio N, Seminerio M, Xu YT, et al. Benzimidazolone-based selective σ2 receptor ligands: Synthesis and pharmacological evaluation. Eur J Med Chem. 2019;165:250–7. https://doi.org/10.1016/j.ejmech.2019.01.019
Yi B, Sahn JJ, Ardestani PM, Evans AK, Scott LL, Chan JZ, et al. Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer’s disease. J Neurochem. 2017;140:561–75. https://doi.org/10.1111/jnc.13917
Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, et al. Alzheimer’s therapeutics targeting amyloid beta 1−42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 2014;9:e111898 https://doi.org/10.1371/journal.pone.0111898
Rishton GM, Look GC, Ni ZJ, Zhang J, Wang Y, Huang Y, et al. Discovery of investigational drug CT1812, an antagonist of the sigma-2 receptor complex for Alzheimer’s disease. ACS Med Chem Lett 2021;12:1389–95. https://doi.org/10.1021/acsmedchemlett.1c00048
https://clinicaltrials.gov/ct2/show/NCT04735536?term=CT1812&draw=2&rank=1
McDonald ES, Doot RK, Young AJ, Schubert EK, Tchou J, Pryma DA, et al. Breast cancer 18F-ISO-1 uptake as a marker of proliferation status. J Nucl Med. 2020;61:665–70. https://doi.org/10.2967/jnumed.119.232363
Sahn JJ, Mejia GL, Ray PR, Martin SF, Price TJ. Sigma 2 receptor/Tmem97 agonists produce long lasting antineuropathic pain effects in mice. ACS Chem Neurosci. 2017;8:1801–11. https://doi.org/10.1021/acschemneuro.7b00200
Guo L, Zhen X. Sigma-2 receptor ligands: neurobiological effects. Curr Med Chem 2015;22:989–1003. https://doi.org/10.2174/0929867322666150114163607
Blass BE, Gao R, Blattner KM, Gordon JC, Pippin DA, Canney DC. Design, synthesis, and evaluation of novel, selective γ-butyrolactones sigma-2 ligands. Med Chem Res. 2021;30:1713–27. https://doi.org/10.1007/s00044-021-02771-0
Blass BE. Basic principles of drug discovery and development second edition, Academic Press, 2021, chapter 5, 257–303, https://doi.org/10.1016/B978-0-12-817214-8.00005-1.
Pajouhesh H, Lenz GR. Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2005;2:541–53. https://doi.org/10.1602/neurorx.2.4.541
Blass BE. Basic Principles of Drug Discovery and Development. 2nd edition. Academic Press; 2021, chapter 6, 305–69, https://doi.org/10.1016/B978-0-12-817214-8.00005-1.
Besnard J, Ruda GF, Setola V, Abecassis K, Rodriguiz RM, Huang XP, et al. Automated design of ligands to polypharmacological profiles. Nature. 2012;492:215–20. https://doi.org/10.1038/nature11691
Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aid Mol Des 2013;7:221–34. https://doi.org/10.1007/s10822-013-9644-8
Schrödinger Release 2022-1: Protein Preparation Wizard; Epik, Schrödinger, LLC, New York, NY, 2021; Impact, Schrödinger, LLC, New York, NY; Prime, Schrödinger, LLC, New York, NY, 2021.
Jacobson MP, Pincus DL, Rapp CS, Day TJF, Honig B, Shaw DE, et al. A hierarchical approach to all-atom protein loop prediction. Proteins: Struct, Funct Bioinforma. 2004;55:351–67. https://doi.org/10.1002/prot.10613
Jacobson MP, Friesner RA, Xiang Z, Honig B. On the role of crystal packing forces in determining protein sidechain conformations. J Mol Biol 2002;320:597–608. https://doi.org/10.1016/s0022-2836(02)00470-9
Schrödinger Release 2022-1: Prime, Schrödinger, LLC, New York, NY, 2021.
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006;49:6177–96. https://doi.org/10.1021/jm051256o
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy. J Med Chem 2004;47:1739–49. https://doi.org/10.1021/jm0306430
Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, et al. Glide: a new approach for rapid, accurate docking and scoring. 2. enrichment factors in database screening. J Med Chem 2004;47:1750–9. https://doi.org/10.1021/jm030644s
Schrödinger Release 2022-1: Glide, Schrödinger, LLC, New York, NY, 2021.
Schrödinger Release 2022-1: LigPrep, Schrödinger, LLC, New York, NY, 2021.
McMasters DR, Torres RA, Crathern SJ, Dooney D, Nachbar RB, Sheridan RP, et al. Inhibition of recombinant cytochrome P450 isoforms 2D6 and 2C9 by diverse drug-like molecules. J Med Chem. 2007;50:3205–13. https://doi.org/10.1021/jm0700060. 14
Acknowledgements
Ki determinations for compound binding to Sigma-1, and Sigma-2 were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. For experimental details please refer to the PDSP web site https://pdsp.unc.edu/ims/investigator/web/. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. TPSA and cLogP values were generated using the Dotmatics software suite (Dotmatics LLC The Old Monastery, Windhill Bishops, Stortford Herts, CW23 2ND UK).
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Blass, B.E., Blattner, K.M., Gordon, J.C. et al. Discovery of novel, selective, functionalized 5-(2-(5-arylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-γ-butyrolactone sigma-2 ligands. Med Chem Res 31, 1209–1223 (2022). https://doi.org/10.1007/s00044-022-02909-8
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DOI: https://doi.org/10.1007/s00044-022-02909-8