8fgq
From Proteopedia
Structure of human endothelial nitric oxide synthase heme domain in complex with 4-(5-(2-(dimethylamino)ethyl)-2,3-difluorophenethyl)-6-methylpyrimidin-2-amine
Structural highlights
FunctionNOS3_HUMAN Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.[1] Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.[2] Publication Abstract from PubMedA series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS), based on a difluorobenzene ring linked to a 2-aminopyridine scaffold with different functionalities at the 4-position, is reported. In our efforts to develop novel nNOS inhibitors for the treatment of neurodegenerative diseases, we discovered 17, which showed excellent potency toward both rat (K(i) 15 nM) and human nNOS (K(i) 19 nM), with 1075-fold selectivity over human eNOS and 115-fold selectivity over human iNOS. 17 also showed excellent permeability (P(e) = 13.7 x 10(-6) cm s(-1)), a low efflux ratio (ER 0.48), along with good metabolic stability in mouse and human liver microsomes, with half-lives of 29 and >60 min, respectively. X-ray cocrystal structures of inhibitors bound with three NOS enzymes, namely, rat nNOS, human nNOS, and human eNOS, revealed detailed structure-activity relationships for the observed potency, selectivity, and permeability properties of the inhibitors. Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors.,Vasu D, Do HT, Li H, Hardy CD, Awasthi A, Poulos TL, Silverman RB J Med Chem. 2023 Jul 27;66(14):9934-9953. doi: 10.1021/acs.jmedchem.3c00782. Epub , 2023 Jul 11. PMID:37433128[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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