Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase.
Inhibitors of neuronal nitric oxide synthase have been proposed as therapeutics for the treatment of different types of neurological disorders. On the basis of a cis-3,4-pyrrolidine scaffold, a series of trans-cyclopropyl- and methyl-containing nNOS inhibitors have been synthesized. The insertion of a rigid electron-withdrawing cyclopropyl ring decreases the basicity of the adjacent amino group, which resulted in decreased inhibitory activity of these inhibitors compared to the parent compound. Nonetheless, three of them exhibited double-digit nanomolar inhibition with high nNOS selectivity on the basis of in vitro enzyme assays. Crystal structures of nNOS and eNOS with these inhibitors bound provide a basis for detailed structure-activity relationship (SAR) studies. The conclusions from these studies will be used as a guide in the future development of selective NOS inhibitors.
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA.
Huiying
H
Li
Fengtian
F
Xue
James M
JM
Kraus
Haitao
H
Ji
Kristin Jansen
KJ
Labby
Jan
J
Mataka
Silvia L
SL
Delker
Pavel
P
Martásek
Linda J
LJ
Roman
Thomas L
TL
Poulos
Richard B
RB
Silverman
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D051379:Mice; D062105:Molecular Docking Simulation; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003521:Cyclopropanes; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C021985:cyclopropene; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III