SC-50605

Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Extensive structure-activity relationship studies, in which a series of heterocyclic replacements for the methyl ketone functional group of SC-41930 was explored, identified SC-50605 (7-[3-[2-(cyclopropylmethyl)-3-methoxy-4- (4-thiazolyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- carboxylic acid) as an optimized analog within a series of thiazoles. SC-50605 was found to be significantly more potent than SC-41930 in LTB4 receptor binding, chemotaxis, and degranulation assays. It also displayed very good activity in animal models of colitis and epidermal inflammation by oral, topical, intravenous, and intracolonic routes of administration. The resolved enantiomers of SC-50605 were obtained by chiral chromatography and both demonstrated good in vitro and in vivo activity. The (+)-isomer (SC-52798) is currently being evaluated as a potential clinical candidate for psoriasis and ulcerative colitis therapy.

Systematic structural modification of peptidoleukotriene antagonists of the o-hydroxyacetophenone class has led to the discovery of certain [[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]alkyl]benzenepropanoic acids and related compounds I (X and Y = O OR CH₂, R = H or [O(CH₂)_nCO₂H, n = 3-8]), which appear to be potent and selective antagonists of the proinflammatory mediator leukotriene B₄.The compounds were tested for inhibition of leukotriene B₄ binding in human neutrophils and as antagonists of leukotriene B₄-induced bronchoconstriction in guinea pigs.