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.

BIOCEV 252 42 Vestec Czech Republic

Department of Biochemistry University of Texas Health Science Center San Antonio Texas 78384 7760 United States

Department of Chemistry Department of Molecular Biosciences Chemistry of Life Processes Institute Center for Molecular Innovation and Drug Discovery Northwestern University 2145 Sheridan Road Evanston Illinois 60208 3113 United States

Department of Pediatrics 1st Faculty of Medicine Charles University 121 08 Prague Czech Republic

Departments of Molecular Biology and Biochemistry Pharmaceutical Sciences and Chemistry University of California Irvine California 92697 3900 United States

State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University Nanjing 210093 People's Republic of China

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