Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa

Disubstituted isoquinolones 2 and 3 have affinity for GPIIb-IIIa and repres ent leads for further structural evaluation. Structure-activity studies cen tered on the bicyclic beta-turn mimic contained in these molecules indicate d that this moiety could accommodate a variety of modifications. Specifical ly, monocyclic, 6,5-bicyclic, and 6,7-bicyclic structures provide compounds with affinity for GPIIb-IIIa. Within the 6,6-series, isoquinoline, tetrali n, tetralone, and benzopyran nuclei yield potent antagonists that are speci fic for GPIIb-IIIa. Attachment of the arginine isostere (benzamidine) to th e supporting nucleus can be accomplished with an ether or amide linkage, al though the latter enhances activity. Several compounds in this series provi ded measurable blood levels after oral dosing. Conversion of the acid moiet y in these molecules to an ester generally provided compounds which gave gr eater systemic exposure after oral administration. Absolute bioavailabiliti es in the rat for the ethyl ester prodrug derivatives of the tetralin, tetr alone, and benzopyran analogues of 3 were 28%, 23%, and 24%, respectively.