Abstract
A number of peptido-leukotriene antagonists coming from a variety of different structural classes have been developed over the last ten years and are in clinical development as anti-asthmatic agents.1, 2, 3 Many of these compounds are complex molecules and we have aimed at developing novel compounds which combine structural simplicity with high oral potency. Compounds of the quinoline type were considered to be suitable target structures for the design of new potent and highly bioavailable LTD4 antagonists.4, 5 The clinically most advanced compound of this type is at present MK-0476 (montelukast sodium).6 The quinoline antagonists, characterized by a substituent in the 2 position consisting of a spacer with 2 atoms, an additional aromatic moiety and a terminal acidic group, show good in vitro and in vivo activity including ease of synthesis. The nature of this acidic residue is of key importance for the pLT antagonist potency of quinoline type antagonists. Combination of the required structural elements led to the synthesis of CGP57698 (4-[3-(7-fluoro-2-quinolinyl-methoxy)phenyl-amino]-2,2-diethyl-4-oxo-buta-noic acid). In CGP57698 the acidic group is derived from succinic acid with two geminal ethyl groups, which are essential for the high potency of CGP57698.
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References
C.D.W. Brooks, and J.B. Summers, Modulators of leukotriene biosynthesis and receptor activation, J. Med. Chem. 39: 2629–2654 (1996).
A. von Sprecher, A. Beck, M. Gerspacher, and M.A. Bray, Peptidoleukotriene antagonists: state of the art, Chimia. 46: 304–311 (1992).
A. von Sprecher, A. Beck, M. Gerspacher, A. Sallmann, G.P. Anderson, N. Subramanian, U. Niederhauser, and M.A. Bray, Strategies in the design of peptidoleukotriene antagonists, J. Lipid Mediators. 6(1–3): 265–73 (1993).
R.A. Galemmo, A. Gavai, and F.-C. Huang, Recent developments in sulphidopeptide leukotriene receptor antagonists, Curr. Opin. Ther. Patents. 811-833 (1992).
J.H. Musser, and A.F. Kreft, Substituted-[2-quinolinyl(bridged)aryl] compounds: modulators of eicosanoid biosynthesis and action, Drugs Future. 15: 73–80 (1990).
M. Labelle, M. Belley, Y. Gareau, J.Y. Gauthier, D. Guay, R. Gordon, S.G. Grossmann, T.R. Jones, Y. Leblanc, M. McAuliffe, C. McFarlane, P. Masson, K.M. Metters, N. Ouimet, D.H. Patrick, H. Piechuta, C. Rochette, N. Sawyer, Y.B. Xiang, C.B. Pickett, A.W. Ford-Hutchinson, R. Zamboni, R.N. Young, Discovery of MK-0476, a potent and orally active leukotriene D 4 receptor antagonist devoid of peroxisomal enzyme induction, Bioorg. Med. Chem. Lett. 5: 283–288 (1995).
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von Sprecher, A. et al. (1997). CGP57698: A Structurally Simple, Highly Potent Peptidoleukotriene (PLT) Antagonist of the Quinoline Type. In: Sinzinger, H., Samuelsson, B., Vane, J.R., Paoletti, R., Ramwell, P., Wong, P.YK. (eds) Recent Advances in Prostaglandin, Thromboxane, and Leukotriene Research. Advances in Experimental Medicine and Biology, vol 433. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1810-9_34
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DOI: https://doi.org/10.1007/978-1-4899-1810-9_34
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