SECOND-GENERATION LEUKOTRIENE-B-4 RECEPTOR ANTAGONISTS RELATED TO SC-41930 - HETEROCYCLIC REPLACEMENT OF THE METHYL KETONE PHARMACOPHORE

Our previous reports have highlighted the first-generation leukotriene B-4 (LTB(4)) receptor antagonist SC-41930 oxy-2-propylphenoxy)propoxy ]-3,4-dihydro-8-propyl- 2H-1-benzopyran-2-carboxylic acid) which has p otent oral, topical, and intracolonic activity in various animal model s of inflammation. Extensive structure-activity relationship studies, in which a series of heterocyclic replacements for the methyl ketone f unctional group of SC-41930 was explored, identified SC-50605 -3,4-dih ydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) as an optimized analo g within a series of thiazoles. SC-50605 was found to be significantly more potent than SC-41930 in LTB(4) receptor binding, chemotaxis, and degranulation assays. It also displayed very good activity in animal models of colitis and epidermal inflammation by oral, topical, intrave nous, and intracolonic routes of administration. The resolved enantiom ers of SC-50605 were obtained by chiral chromatography and both demons trated good in vitro and in vivo activity. The(+)-isomer (SC-52798) is currently being evaluated as a potential clinical candidate for psori asis and ulcerative colitis therapy.