Work

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

Year: 2018

Type: article

Abstract: 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 IC 50 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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.8b00374

Authors: John M. Humphrey, Matthew Movsesian, Christopher W. am Ende, Stacey L. Becker, Thomas A. Chappie, Stephen Jenkinson, Jennifer L. Liras, Spiros Liras, Christine Orozco, Jayvardhan Pandit, Felix F. Vajdos, Fabrice Vandeput, Eddie Yang, Frank S. Menniti

Institutions: Pfizer (United States), University of Utah, University of Rhode Island

Language: English

Topic: Phosphodiesterase function and regulation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: U.S. Department of Energy, U.S. Department of Veterans Affairs, Office of Science, Michigan Technology Tri-Corridor, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Argonne National Laboratory

Awards: G102163711, Signal Transduction at Fertilization, G107546177, G1313983767, G1664757510, G1947107004, G2287611682, G262962599, G3075337988, G3329398301, G416541740, G4773269573, G498139845, G5906309288, G6848031779, G6918803902, G969889393, G993149817

OpenAlex ID: W2801201828

FWCI: 0.859

Cites: 18

Cited by: 32

Related to: 10