Abstract
LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl] ethanone, is an orally active antagonist of LTD4- and LTE4-induced responses in a variety of test systems. We prepared a new series of LT antagonists based on a proposed model of LY171883 binding to the LTE4 receptor in which then-propyl and tetrazole moieties of LY171883 occupy those parts of the receptor to which the C1-C5 chain and the cysteinyl carboxyl of LTE4 bind, respectively. The new compounds have an acidic function corresponding to the glycine carboxyl of LTD4 linked through a heterocyclic group which is proposed to bind to the LTD4 receptor where the cysteinyl glycine amide bond of LTD4 binds. LY203647, 1-[2-hydroxy-3-propyl-4-[4-[2-[4-(1H-tetrazol-5-yl) butyl]-2H-tetrazol-5-yl]butoxy]phenyl] ethanone, showed good LTD4 antagonist activity with a suitable pharmacologic and toxicologic profile and has been chosen for clinical evaluation.
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J. H. Fleisch, L. E. Rinkema, C. A. Whitesitt and W. S. Marshall,Development of cysteinyl leukotriene receptor antagonist. InAdvances in Inflammation Research. (Eds. A. Lewis et al.) pp. 173–189, Raven Press, New York 1988.
L. E. Rinkema, C. R. Roman and J. H. Fleisch,Pharmacologic analysis of LY171883 as a leukotriene E 4 (LTE 4)receptor antagonist. Fed. Proc.46, 1461 (1987).
S. A. Silbaugh, P. W. Stengel, P. A. Pechous and W. S. Marshall,Reversal of LTD 4-and LTE 4-induced airway constriction in the guinea pig. Am. Rev. Resp. Dis.137, 374 (1988).
W. S. Marshall, T. Goodson, G. J. Cullinan, D. Swanson-Bean, K. D. Haisch, L. E. Rinkema and J. H. Fleisch,Leukotriene receptor antagonists. 1. Synthesis and structure-activity relationships of alkoxyacetophenone derivatives. J. Med. Chem.30, 682–689 (1987).
J. M. Van Rossum,Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch. Int. Pharmacodyn. Ther.143, 229–330 (1963).
R. F. Furchgott,The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. InHandbook of Experimental Pharmacology, vol. 33. (Eds. O. Eichler, A. Farah, H. Herken and A. D. Welch) pp. 283–335, Springer, New York 1972.
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Marshall, W.S., Sigmund, S.K., Whitesitt, C.A. et al. Leukotriene (LT) receptor antagonists. Heterocycle-linked tetrazoles and carboxylic acids. LY203647. Agents and Actions 27, 309–312 (1989). https://doi.org/10.1007/BF01972807
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DOI: https://doi.org/10.1007/BF01972807