@article{e95b7e716bb647c3a4ab040d05ed6ea7,
title = "Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors",
abstract = "Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.",
author = "Pensa, {Anthony V.} and Cinelli, {Maris A.} and Huiying Li and Georges Chreifi and Paramita Mukherjee and Roman, {Linda J.} and Pavel Mart{\'a}sek and Poulos, {Thomas L.} and Silverman, {Richard B.}",
note = "Funding Information: We thank the National Institutes of Health (R01GM049725, to R.B.S., GM057353 to T.L.P., and F32GM109667 to M.A.C.) for generous support of this work. A.P. was supported by a Lambert Fellowship (Chemistry of Life Processes Institute, Northwestern University) and by the Katherine L. Kreighbaum Scholarship (Northwestern University). L.J.R. is currently supported on NIH GM081568 and NSF grant 13-573. P.M. is supported by grants UNCE 204011 and PRVOUK P24/ LF1/3 from Charles University, Prague, Czech Republic. A.P. and M.A.C. thank Saman Shafaie and Dr. S. Habibi Goudarzi for assistance with HRMS experiments, and Drs. Arsen Gaisin and Neha Malik of the Center for Molecular Innovation and Drug Discovery (Northwestern University) for valuable assistance with preparative HPLC. This work made use of IMSERC at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF NNCI-1542205), the State of Illinois, and the International Institute for Nanotechnology (IIN). H.L. thanks Carla Plaza for her assistance in NOS protein expression and purification; the purified samples were used in both crystallography and enzyme assays. We also thank the SSRL and ALS beamline staff for their support during remote X-ray diffraction data collection. Off-target Ki determinations (CNS counterscreening) were generously provided by the National Institute of Mental Health{\textquoteright}s Psychoactive Drug Screening Program, (contract no. HHSN-271-2013-00017-C, NIMH PDSP), directed by Dr. Bryan L. Roth (University of North Carolina at Chapel Hill) and project officer Jamie Driscoll (NIH). Publisher Copyright: {\textcopyright} 2017 American Chemical Society.",
year = "2017",
month = aug,
day = "24",
doi = "10.1021/acs.jmedchem.7b00835",
language = "English (US)",
volume = "60",
pages = "7146--7165",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "16",
}