SYNTHESIS OF L-THIOCITRULLINE, L-HOMOTHIOCITRULLINE, AND S-METHYL-L-THIOCITRULLINE - A NEW CLASS OF POTENT NITRIC-OXIDE SYNTHASE INHIBITORS

Nitric oxide synthase catalyzes the NADPH- and O-2-dependent conversion of L-arginine to L-citrulline and nitric oxide. L-Thiocitrulline, L-homothiocitrulline, and S-methyl-L-thiocitrulline, novel citrulline analogs, have been synthesized and are shown to be potent inhibitors of both the constitutive brain and the inducible smooth muscle isoforms of nitric oxide synthase. Although many N-omega-monosubstituted arginine derivatives inhibit nitric oxide synthase, inhibitory citrulline derivatives have not previously been reported. S-Methyl-L-thiocitrulline is significantly more potent than N-omega-methyl-L-arginine, the prototypic nitric oxide synthase inhibitor.