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2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity

Title
2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity
Authors
Kang, SoosungLi, HuiyingTang, WeiMartasek, PavelRoman, Linda J.Poulos, Thomas L.Silverman, Richard B.
Ewha Authors
강수성
Issue Date
2015
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0022-2623JCR Link

1520-4804JCR Link
Citation
JOURNAL OF MEDICINAL CHEMISTRY vol. 58, no. 14, pp. 5548 - 5560
Publisher
AMER CHEMICAL SOC
Indexed
SCI; SCIE; SCOPUS WOS
Document Type
Article
Abstract
We have analyzed a recently obtained crystal structure of human neuronal nitric Oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and tat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and, conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected) inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits K-i values of 24 and SS nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.
DOI
10.1021/acs.jmedchem.5b00573
Appears in Collections:
약학대학 > 약학과 > Journal papers
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