Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1

Autor:	Eddie Yang, Jennifer L. Liras, Christine C. Orozco, Christopher W. am Ende, Matthew A. Movsesian, Jayvardhan Pandit, John M. Humphrey, Stephen Jenkinson, Frank S. Menniti, Thomas Allen Chappie, Spiros Liras, Stacey L. Becker, Felix Vajdos, Fabrice Vandeput
Rok vydání:	2018
Předmět:	0301 basic medicine Models Molecular Phosphodiesterase Inhibitors Protein Conformation 030204 cardiovascular system & hematology PDE1 Human myocardium Cocrystal 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery Quinazoline Ic50 values Cyclic AMP Humans Cyclic nucleotide phosphodiesterase Molecular Structure Myocardium Cyclic Nucleotide Phosphodiesterases Type 1 030104 developmental biology chemistry Biochemistry Plasma concentration Quinazolines Molecular Medicine
Zdroj:	Journal of medicinal chemistry. 61(10)
ISSN:	1520-4804
Popis:	We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor (S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aad70863e6c50adf198b09386b95c77c https://pubmed.ncbi.nlm.nih.gov/29718668 Zobrazit plný text záznamu