ABSTRACT
A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.
Subject(s)
Anticoagulants/therapeutic use , Antithrombin III/therapeutic use , Cyclohexylamines/therapeutic use , Drug Design , Administration, Oral , Binding Sites , Binding, Competitive , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Intestinal Absorption/drug effects , Kinetics , Molecular Structure , Platelet Membrane Glycoproteins , Protein Conformation , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anticoagulants/chemistry , Anticoagulants/pharmacology , Factor Xa Inhibitors , Indoles/pharmacology , Propionates/pharmacology , Thiazoles/pharmacology , Administration, Oral , Animals , Anticoagulants/chemical synthesis , Biological Availability , Crystallography, X-Ray , Factor Xa/metabolism , Haplorhini , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Naphthalenes/pharmacology , Propionates/chemical synthesis , Propionates/chemistry , Propionates/pharmacokinetics , Protein Binding , Thiazoles/chemistry , Thiazoles/pharmacokineticsABSTRACT
Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.
