Synthesis and evaluation of dipeptide amides containing N-omega-nitroarginine and D-2,4-diaminobutyric acids as inhibitors of neuronal nitric oxide synthase

Selective inhibition of the isoforms of nitric oxide synthase (NOS) could b e beneficial in the treatment of certain disease states arising from the ov erproduction of nitric oxide by NOS. Recently, we reported dipeptide amides containing a basic amine side chain as potent and selective inhibitors of neuronal NOS (Huang, H. et al. (1999) J. Med. Chem., 42, 3147). The most po tent nNOS inhibitor among these compounds is L-Arg (NO2)-L-Dbu-NH2 (1) (K-i = 130 nM), which also exhibits the highest selectivity over eNOS (> 1500-f old). The D,D-dipeptide, D-LyS-D-Arg(NO2)-NH2 (3) also shows high potency a nd selectivity. Here the dipeptide amides containing Arg(NO2) and D-Dbu (9- 12) were synthesized and evaluated. They are all modest inhibitors of nNOS, but poor inhibitors of eNOS and iNOS. D-DbU-D-Arg(NO2)-NH2 (12) exhibits d ecreased inhibitory potency as compared with 3. A hypothesis regarding the binding at the active site of nNOS is proposed to explain the potency diffe rences between the L- and D-form dipeptide amides.