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.

Article Details

Citation

Copy to clipboard

Nagata T, Yoshino T, Haginoya N, Yoshikawa K, Nagamochi M, Kobayashi S, Komoriya S, Yokomizo A, Muto R, Yamaguchi M, Osanai K, Suzuki M, Kanno H

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.

Bioorg Med Chem. 2009 Feb 1;17(3):1193-206. doi: 10.1016/j.bmc.2008.12.037. Epub 2008 Dec 24.

PubMed ID

19128974 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N-((1R,2S)-2-(5-CHLORO-1H-INDOLE-2-CARBOXAMIDO)CYCLOHEXYL)-5-METHYL-4,5,6,7-TETRAHYDROTHIAZOLO[5,4-C]PYRIDINE-2-CARBOXAMIDE	Coagulation factor X	IC 50 (nM)	16	N/A	N/A	Details