Journal of Medicinal Chemistry p. 4913 - 4925 (2016)
Update date:2022-07-29
Topics:
Wang, Heng-Yen
Qin, Yajuan
Li, Huiying
Roman, Linda J.
Martásek, Pavel
Poulos, Thomas L.
Silverman, Richard B.
Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.
View MoreJiYi Chemical (Beijing) Co., Ltd.
Contact:+86-10-89385733
Address:Shilou Town of Fangshan District, Beijing
Contact:86-25-51817806
Address:No. 216, middle longpan road, jincheng tower, floor 21-22, nanjing ,china
Shandong united-rising pharmaceutical cooperation.,ltd.
Contact:008653187965009
Address:171No., Jing5 Road, Shizhong District, Jinan, China
Shanghai ZaiQi Bio-Tech Co., Ltd.,
Contact:+86-21-5482 4098
Address:Bldg. No.7, No.201 MinYi Rd,Songjiang CaoHeJing High-Tech Park Shanghai 201516 P,R,China
Nanjing Xi Ze Biological Technology Co., Ltd
Contact:86-025-66023220
Address:Address: Nanjin Qixia District Maigaoqiao R & D base in Pioneer Park Chun Yin Road 18-A928
Doi:10.1055/s-2001-16773
(2001)Doi:10.1002/chem.201304063
(2014)Doi:10.1039/f19827800347
(1982)Doi:10.1016/S0040-4039(01)84944-3
(1972)Doi:10.1021/ja01609a033
(1955)Doi:10.1016/j.jinorgbio.2010.03.013
(2010)