Discovery of N-[(1 R,2 S,5 S)-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

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 inh...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-02, Vol.17 (3), p.1193-1206
Main Authors: Nagata, Tsutomu, Yoshino, Toshiharu, Haginoya, Noriyasu, Yoshikawa, Kenji, Nagamochi, Masatoshi, Kobayashi, Syozo, Komoriya, Satoshi, Yokomizo, Aki, Muto, Ryo, Yamaguchi, Mitsuhiro, Osanai, Ken, Suzuki, Makoto, Kanno, Hideyuki
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anticoagulant
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
Lipophilicity
Naphthalenes - chemical synthesis
Naphthalenes - chemistry
Naphthalenes - pharmacology
Non-amidino compound
Oral bioavailability
Propionates - chemical synthesis
Propionates - chemistry
Propionates - pharmacokinetics
Propionates - pharmacology
Protein Binding
Thiazoles - chemistry
Thiazoles - pharmacokinetics
Thiazoles - pharmacology
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.12.037