Discovery of N-((1R,2S,5S)-2-{((5-chloroindol-2-yl)carbonyl)amino}-5-(dimethylcarbamoyl)cycloh exyl)-5-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridine-2-carboxamide hydrochloride: a novel, potent and orally active direct inhibitor of factor Xa.

摘要

In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.