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

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.