Synthesis and Conformational Analysis of a Non-Amidine Factor Xa Inhibitor That Incorporates 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine as S4 Binding Element

Citations Over TimeTop 12% of 2004 papers

Abstract

Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expected to be S4 binding element. Among this series, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine type 61 displayed orally potent anti-fXa activity and evident prolongation of prothrombin time (PT) with the moderate bioavailability in rats. The X-ray crystal analysis afforded an obvious binding mode that 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 6-chloronaphthalene respectively bound to S4 and S1 subsites. In this X-ray study, we discovered a novel intramolecular S-O close contact. Ab initio energy calculations of model compounds deduced that conformers with the most close S-O proximity were most stable. The Mulliken population analysis proposed that this energy profile was caused by both of electrostatic S-O affinity and N-O repulsion. The results of these calculations and X-ray analysis suggested a possibility that the restricted conformation effected the affinity to S4 subsite of fXa.

Related Papers

• → Probing effect of weak H-bonding on conformational change in ionic liquid: Experimental and DFT studies(2018)12 cited
• → Structural information from OH stretching vibrations—XVII. On the different conformers in benzylalcohols and anthracylmethanols(1986)22 cited
• → Relative energies, stereoelectronic interactions and conformational interconversions in silathiacyclohexanes(2004)15 cited
• → Effects of side chains in gas-phase amino acids: Conformational analysis and relative stabilities(2009)7 cited
• → Conformation and vibrational spectra of 1,2-diisocyanoethane(1982)7 cited