Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. Identification of 2-azabicyclo[4.1.0]heptan-3-imines.

Abstract Further chemical modification of 2-iminopiperidines fused to cyclopropane rings was performed. Optically active isomers 2 and 13 were synthesized and their biological activity was evaluated. Compound 2 exhibited greater potency and more isoform selectivity than enantiomer 13 in the iNOS inhibition assay. One of the gem -chlorines on the fused cyclopropane moiety of 2 was eliminated to produce 3 , which showed reduced potency for iNOS inhibition, as well as 4 with an increased potency. The isoform selectivity of 4 was also much higher than that of 3 . This was also true for the corresponding methyl derivatives 6 – 9 . The structure–activity relationship (SAR) study and computer aided docking study of the most optimized structure 4 with human iNOS will also be reported.