5FVX

Structure of human nNOS R354A G357D mutant heme domain in complex with with 6-(2-(5-(3-(DIMETHYLAMINO)PROPYL) PYRIDIN-3-YL)ETHYL)-4-METHYLPYRIDIN-2-AMINE

Summary for 5FVX

• Entry DOI: 10.2210/pdb5fvx/pdb
• Related: 5FVO 5FVP 5FVQ 5FVR 5FVS 5FVT 5FVU 5FVV 5FVW 5FVY 5FVZ 5FW0
• Descriptor: NITRIC OXIDE SYNTHASE, BRAIN, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (6 entities in total)
• Functional Keywords: oxidoreductase, nitric oxide synthase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane, sarcolemma; Peripheral membrane protein: P29475
• Total number of polymer chains: 2
• Total formula weight: 99946.72

Authors

Li, H.,Poulos, T.L. (deposition date: 2016-02-10, release date: 2016-04-20, Last modification date: 2024-05-08)

Primary citation

Wang, H.,Qin, Y.,Li, H.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.
J.Med.Chem., 59:4913-, 2016

PubMed Abstract: 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.

PubMed: 27050842
DOI: 10.1021/ACS.JMEDCHEM.6B00273

Experimental method

X-RAY DIFFRACTION (2.3 Å)