Synthesis of guanidino analogues as potential nitric oxide synthase inhibitors

Abstract

Overproduction of nitric oxide by neuronal nitric oxide synthase leads to neurodegeneration. Various guanidino analogues were synthesised through solution and solid phase syntheses. 63 compounds were synthesised and evaluated for nNOS selective inhibition and neuroprotection. Upon screening, N1-benzyl-N2-nitroguanidines emerged as lead series, from which N1-(diphenyl)methyl-N2-nitroguanidine was the most potent nNOS selective inhibitor (IC50 58A?5 microM) with moderate neuroprotective activity. The results suggested that the region adjacent to the guanidino binding site of nNOS is hydrophobic and can accommodate bulkier binding groups than those of the other NOS isoforms. Thus a size-exclusion mechanism is the key to selective nNOS inhibition.