Potent and selective conformationally restricted neuronal nitric oxide synthase inhibitors.
Selective inhibition of the isoforms of nitric oxide synthase (NOS) in pathologically elevated synthesis of nitric oxide has great therapeutic potential. We previously reported nitroarginine-containing dipeptide amides and some peptidomimetic analogues as potent and selective inhibitors of neuronal NOS (nNOS). Here we report conformationally restricted dipeptides derived from the dipeptide L-Arg(NO2)-L-Dbu-NH2 (8). The selectivities for nNOS over endothelial NOS and inducible NOS of the most potent nNOS inhibitor (10a) among these compounds are comparable to that of the parent compound. An unsubstituted amide bond is necessary for potency against nNOS. The stereochemistry of compound 10a was optimum for potency and selectivity and thus provides the binding conformation of the parent compound with nNOS.
Gómez-Vidal
José A
JA
Department of Chemistry, Drug Discovery Program, Northwestern University, Evanston, Illinois 60208-3113, USA.
Martásek
Pavel
P
Roman
Linda J
LJ
Silverman
Richard B
RB
D000818:Animals; D002417:Cattle; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D051379:Mice; D008968:Molecular Conformation; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C482799:4-N-nitroarginyl-4-aminoprolinamide; D004151:Dipeptides; D007527:Isoenzymes; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C496315:Nos3 protein, mouse; C496316:Nos3 protein, rat