- Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker
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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.
- Wang, Heng-Yen,Qin, Yajuan,Li, Huiying,Roman, Linda J.,Martásek, Pavel,Poulos, Thomas L.,Silverman, Richard B.
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supporting information
p. 4913 - 4925
(2016/06/13)
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- INHIBITORS OF FATTY ACID AMIDE HYDROLASE
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Provided herein are compounds of formula (I): or pharmaceutically acceptable salts, solvates or prodrugs thereof or mixtures thereof, wherein Z1, Z2, X1, X2, X3, R1, R2 R3/
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Page/Page column 63; 65
(2010/11/03)
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- 4-CARBOX PYRAZOLE DERIVATES USEFUL AS ANTI-VIRAL AGENTS
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Novel antiviral compounds of Formula (I) : wherein: A represents hydroxy; R1 represents aryl, heteroaryl bonded through a ring carbon atom, or heterocyclyl bonded through a ring carbon atom, C1-6alkyl or -C5-9cycloalkyl, each of which may be optionally su
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Page/Page column 62
(2010/02/14)
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