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
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Administration, Oral
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Animals
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Anticoagulants / chemical synthesis
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Anticoagulants / chemistry*
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Anticoagulants / pharmacology*
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Biological Availability
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Crystallography, X-Ray
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Factor Xa / metabolism
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Factor Xa Inhibitors*
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Haplorhini
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Humans
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Indoles / chemistry
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Naphthalenes / chemical synthesis
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Naphthalenes / chemistry
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Naphthalenes / pharmacology
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Propionates / chemical synthesis
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Propionates / chemistry
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Propionates / pharmacokinetics
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Propionates / pharmacology*
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Protein Binding
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Thiazoles / chemistry
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology*
Substances
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(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid
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Anticoagulants
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Factor Xa Inhibitors
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Indoles
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N-(2-(((5-chloroindol-2-yl)carbonyl)amino)-5-(dimethylcarbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridine-2-carboxamide
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Naphthalenes
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Propionates
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Thiazoles
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Factor Xa