Hideyuki Kanno

Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part II: Exploration of 6–6 fused rings as alternative S1 moieties

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.

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.

In the early 1990s, 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.

Stereoselective synthesis and biological evaluation of 3,4-diaminocyclohexanecarboxylic acid derivatives as factor Xa inhibitors.

There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.

2-Aminomethylphenylamine as a novel scaffold for factor Xa inhibitor

We have been researching orally active factor Xa inhibitor for a long time. We explored the new diamine linker using effective ligands to obtain a new attractive original scaffold 2-aminomethylphenylamine derivative. Compound 1D showed very strong in vitro and in vivo factor Xa inhibitory activity, as well as favorable PK profiles in po administration to monkeys.

Potent inhibitors of neutral endopeptidase. 2-Biphenyl- methylglutaric acid amide derivatives

Abstract A series of glutaric acid amide derivatives were synthesized and tested for NEP inhibitory activity. Compounds 14a, 14b, 16a and 22, with a biphenylmethyl group at P′1 position, showed potent inhibitory activity.

Diastereoselective palladium(0)-catalyzed reactions of lithium enolates of chiral N-acyloxazolidinones. Asymmetric synthesis of 2-substituted (E)-4-alkylidenepentanedioates

The palladium(0)-catalyzed reactions of lithium enolates 1 of N-acyloxazolidinones with 3-acetoxy-2-methylenealkanoates 2, easily prepared via DABCO-catalyzed coupling of corresponding aldehydes with acrylates, proceeded diastereoselectively and regioselectively to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones3, useful intermediates of metallopeptidase inhibitors.

Design, synthesis and SAR of novel ethylenediamine and phenylenediamine derivatives as factor Xa inhibitors.

We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy.

Diastereoselective addition-elimination reactions of lithium enolates of chiral N-acyloxazolidinones with 2-methylene-3-phenoxyalkanoates

Abstract Addition-elimination reactions of lithium enolates 2 of N-acyloxazolidinones with 2-methylene-3-phenoxyalkanoates 3 and 10 proceeded diastereoselectively and regiospecifically to give chiral N-[( E )-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones 4 and 12a , which are useful intermediates for the synthesis of enzyme inhibitors.

Orally active zwitterionic factor Xa inhibitors with long duration of action.

We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-β pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.