Synthesis and structure-activity relationship studies of a series of 5-aryl-4,6-dithianonanedioic acids and related compounds: a novel class of leukotriene antagonists

• Published in: Journal of medicinal chemistry Vol. 29; no. 8; pp. 1442 - 1452
• Main Authors: Perchonock, Carl D, Uzinskas, Irene, McCarthy, Mary E, Erhard, Karl F, Gleason, John G, Wasserman, Martin A, Muccitelli, Roseanna M, DeVan, Jeris F, Tucker, Stephanie S
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-08-1986
• Subjects: Alkynes - chemical synthesis; Alkynes - pharmacology; Animals; Binding, Competitive; Bronchi - drug effects; Chemistry; Dicarboxylic Acids - chemical synthesis; Dicarboxylic Acids - pharmacology; Exact sciences and technology; Guinea Pigs; Magnetic Resonance Spectroscopy; Muscle Contraction - drug effects; Noncondensed benzenic compounds; Organic chemistry; Preparations and properties; Receptors, Leukotriene; Receptors, Prostaglandin - metabolism; SRS-A - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; Sulfides - chemical synthesis; Sulfides - pharmacology; Trachea - drug effects; Aliphatic compound; Rodentia; Saturated compound; Smooth muscle; Biological activity; Vertebrata; Dithioacetal; Mammalia; Guinea pig; Structure activity relation; Carboxylic acid; Leucotriene D4; Benzenic compound; Antagonist
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00158a021

A series of 5-alkynyl- and 5-aryl-4,6-dithianonanedioic acids and related compounds has been prepared for evaluation of leukotriene antagonist activity. The alkynyl compounds were prepared by thioacetal exchange from the corresponding acetylenic acetals. The aryl derivatives were synthesized from the appropriate benzaldehydes, most of which were prepared by one of three general routes: Meyers' oxazolin method, a palladium coupling procedure, and a hydroxybenzaldehyde alkylation. The analogues were examined in vitro for their ability to antagonize an LTD4-induced contraction of isolated guinea pig tracheal smooth muscle and to compete with [3H]LTD4 for receptor sites on guinea pig lung membrane. A number of structure-activity relationships have emerged from this study. There is an optimal chain length of 10-12 atoms (or its equivalent) in the lipid tail and two methylenes in the polar region. In the aromatic series, the ortho- and meta-substituted compounds have comparable activity, whereas the para derivatives are inactive. Substitution in the aromatic ring and lipid tail is generally well tolerated, with the terminal phenyl (6) and acetylene (33) analogues having especially good activity. Conformational restriction of either the polar region or lipid tail produced compounds devoid of activity. A number of selected analogues were also evaluated in vivo as antagonists of LTD4-induced bronchoconstriction in the guinea pig. The data established these compounds as a novel class of leukotriene antagonists with potential utility for the treatment of asthma and other immediate hypersensitivity diseases.