GPIIB IIIA INTEGRIN ANTAGONISTS WITH THE NEW CONFORMATIONAL RESTRICTION UNIT, TRISUBSTITUTED BETA-AMINO ACID-DERIVATIVES, AND A SUBSTITUTEDBENZAMIDINE STRUCTURE/

Ethyl N- [3 l)amino-2,2-dimethylpentanoyl]piperidine-4-acetate 40 (NSL -96184:) is a highly potent and orally active fibrinogen receptor anta gonist, which is characterized by the presence of the trisubstituted b eta-amino acid residue, 3 -ethyl-2,2-dimethyl-beta-alanine. This compo und was developed on the basis of the SAR study of 2,2-dimethyl-3-phen ylpropionyl]piperidine-4-acetic acid 1 (NSL-95301) with the derivatiza tion focused on the central trisubstituted beta-amino acid unit as wel l as the basic amidinobenzoyl unit, and the esterification of the carb oxyl group for prodrug composition, Compound 1, which was report;ed in our previous study, was discovered by the application of combinatoria l chemistry. The molecular modeling study suggests that the trisubstit uted beta-amino acid unit is responsible for fixing the molecule to it s active conformation. Compound 40 showed an excellent profile in the in vitro and in vivo studies for its human platelet aggregation inhibi tory activity and oral availability in guinea pigs. This oral availabi lity largely depends on the modification of the amidino group with a c yclic secondary amine, i.e., thiazolidine in 40. In in vivo studies, t he onset of the antiplatelet action of 40 is very fast after oral admi nistration, whereas its duration of action is relatively short. These results suggest that 40 has an excellent therapeutic potential, especi ally for antithrombotic treatment in the acute phase. 3-Substituted-2, 2-dimethyl-beta-amino acid residues would serve as new and useful line ar templates to restrict the conformational flexibility of peptidomime tics.