2-aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution.
4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.
Connolly
Stephen
S
Medicinal Chemistry, Discovery BioScience, Molecular Biology and Physical and Metabolic Sciences Departments, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics LE11 5RH, U.K. steve.connolly@astrazeneca.com
Aberg
Anders
A
Arvai
Andrew
A
Beaton
Haydn G
HG
Cheshire
David R
DR
Cook
Anthony R
AR
Cooper
Sally
S
Cox
David
D
Hamley
Peter
P
Mallinder
Phil
P
Millichip
Ian
I
Nicholls
David J
DJ
Rosenfeld
Robin J
RJ
St-Gallay
Stephen A
SA
Tainer
John
J
Tinker
Alan C
AC
Wallace
Alan V
AV
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D018360:Crystallography, X-Ray; D051379:Mice; D008958:Models, Molecular; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052247:Nitric Oxide Synthase Type II
D000631:Aminopyridines; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse