Discovery of N-[(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(dimethylcarbamoyl)cyclohexyl]-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.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Anticoagulants / chemical synthesis
  • Anticoagulants / chemistry*
  • Anticoagulants / pharmacology*
  • Biological Availability
  • Crystallography, X-Ray
  • Factor Xa / metabolism
  • Factor Xa Inhibitors*
  • Haplorhini
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacokinetics
  • Indoles / pharmacology*
  • Naphthalenes / chemical synthesis
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Propionates / chemical synthesis
  • Propionates / chemistry
  • Propionates / pharmacokinetics
  • Propionates / pharmacology*
  • Protein Binding
  • Thiazoles / chemistry
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology*

Substances

  • (2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid
  • Anticoagulants
  • Factor Xa Inhibitors
  • Indoles
  • N-(2-(((5-chloroindol-2-yl)carbonyl)amino)-5-(dimethylcarbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridine-2-carboxamide
  • Naphthalenes
  • Propionates
  • Thiazoles
  • Factor Xa