Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives.
Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((±)-32 and (±)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2''-(3'''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437 - 5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, and Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.
Haitao
H
Ji
Silvia L
SL
Delker
Huiying
H
Li
Pavel
P
Martásek
Linda J
LJ
Roman
Thomas L
TL
Poulos
Richard B
RB
Silverman
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D007527:Isoenzymes; D011759:Pyrrolidines; D052248:Nitric Oxide Synthase Type I