NEW PLATELET FIBRINOGEN RECEPTOR GLYCOPROTEIN IIB-IIIA ANTAGONISTS - ORALLY-ACTIVE SERIES OF N-ALKYLATED AMIDINES WITH A 6,6-BICYCLIC TEMPLATE

The design, synthesis, and pharmacological evaluation of (S)-(-)-ethyl enzamido]-3,4-dihydro-2H-1-benzopyran-3-yl]acetate hydrochloride ((S) -4 . HCl, MS-180), an orally active glycoprotein IIb-IIIa (GPIIb-IIIa) antagonist, are reported. Pharmacophore mapping of amidino and carbox yl groups of already known GPIIb-IIIa antagonists led to the synthesis of nine amidino acids containing 6,6-bicyclic ring skeletons (10a-i). Among them, the compounds 10a,c,e having an amide bond and 1,2,3,4-te trahydronaphthalene or 3,4-dihydro-2H-1-benzopyran skeleton showed mar ked inhibitions with IC50 values of 46-57 nM in human platelet aggrega tion assay in vitro, but low oral activities. N-Alkylation of the amid ino group coupled with the ester prodrug approach afforded MS-180 ((S) -4 . HCl), which generates in vivo the corresponding carboxylic acid ( S)-3 as an active species. In vitro, (S)-3 inhibited ADP-induced aggre gation of guinea pig, dog, and human platelets (IC50 = 110, 253, and 3 5 nM, respectively) and inhibited the binding of fibrinogen to immobil ized GPIIb-IIIa of human platelets (IC50 = 0.12 nM). After oral admini stration of MS-180 ((S)-4 . HCl) to fasted beagle dog, ex vivo inhibit ion of platelet aggregation was observed. The maximal inhibitions were observed 2-4 h after dosing with dose dependency (60% inhibition at a dose of 1 mg/kg, 85% at 3 mg/kg, and 100% at 10 mg/kg, respectively) and the extent of the inhibitions paralleled the plasma concentration of the active species (S)-3. On the basis of these studies, we selecte d MS-180 ((S)-4 . HCl) as a candidate for clinical evaluation as a dru g for the treatment and prevention of thrombosis in patients.