TY - JOUR
T1 - 2-Aminopyridines with a Truncated Side Chain to Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity
AU - Kang, Soosung
AU - Li, Huiying
AU - Tang, Wei
AU - Martásek, Pavel
AU - Roman, Linda J.
AU - Poulos, Thomas L.
AU - Silverman, Richard B.
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/7/23
Y1 - 2015/7/23
N2 - 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 rat 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 Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.
AB - 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 rat 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 Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.
UR - http://www.scopus.com/inward/record.url?scp=84936811376&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.5b00573
DO - 10.1021/acs.jmedchem.5b00573
M3 - Article
C2 - 26120733
AN - SCOPUS:84936811376
SN - 0022-2623
VL - 58
SP - 5548
EP - 5560
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -