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 be beneficial in the treatment of certain disease states arising from the overproduction 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 potent nNOS inhibitor among these compounds is L-ArgNO2-L-Dbu-NH2 (1) (Ki = 130 nM), which also exhibits the highest selectivity over eNOS (> 1500-fold). The D,D-dipeptide, D-Lys-D-ArgNO2-NH2 (3) also shows high potency and selectivity. Here the dipeptide amides containing ArgNO2 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-ArgNO2-NH2 (12) exhibits decreased inhibitory potency as compared with 3. A hypothesis regarding the binding at the active site of nNOS is proposed to explain the potency differences between the L- and D-form dipeptide amides.
Huang
H
H
Department of Chemistry and Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208-3113, USA.
Martásek
P
P
Roman
L J
LJ
Silverman
R B
RB
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D000613:Aminobutyrates / Q000032:analysis / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D019335:Nitroarginine / Q000032:analysis / Q000737:chemistry
D000577:Amides; D000613:Aminobutyrates; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019335:Nitroarginine; C005959:2,4-diaminobutyric acid; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I