Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. synthesis and biological evaluation of dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines.

Abstract The process of discovery and biological evaluation of α,β-unsaturated cyclic amidines, as selective inhibitors of inducible nitric oxide synthase (iNOS), is reported. Dihydropyridin-2(1 H )-imines and 1,5,6,7-tetrahydro- 2H -azepin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide synthase inhibition assay. Compounds 1 , 5 , 6 , 8 – 12 and 16 exhibited potent inhibition of iNOS. Among these, compounds 6 , 7 , 10 , 11 and 16 showed 5- to 19-fold isoform selectivity. Compounds 1 , 6 , 10 , 11 and 16 also showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 6 showed excellent bioavailability (BA) in rats when administered orally. Full details are presented here, including the structure–activity relationship (SAR) studies, the chemistry of these compounds, and the pharmacokinetic data and the computer-aided docking study of 10 with hiNOS.