SUBSTITUTED N-PHENYLISOTHIOUREAS - POTENT INHIBITORS OF HUMAN NITRIC-OXIDE SYNTHASE WITH NEURONAL ISOFORM SELECTIVITY

S-Ethyl N-phenylisothiourea (4) has been found to be a potent inhibito r of both the human constitutive and inducible isoforms of nitric oxid e synthase. A series of substituted N-phenylisothiourea analogues was synthesized to investigate the structure-activity relationship of this class of inhibitor. Each analogue was evaluated for human isoform sel ectivity. One analogue, S-ethyl N-[4-(trifluoromethyl)phenyl]isothiour ea (39), exhibited 115-fold and 29-fold selectivity for the neuronal i soform versus the inducible and endothelial derived constitutive isofo rms, respectively. Studies have shown the substituted N-phenylisothiou rea 39 binds competitively with L-arginine.