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

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

Open Access

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

Author(s) -

John M. Humphrey,

Matthew A. Movsesian,

Christopher W. am Ende,

Stacey L. Becker,

Thomas A. Chappie,

Stephen Jenkinson,

Jennifer L. Liras,

Spiros Liras,

Christine C. Orozco,

Jayvardhan Pandit,

F.F. Vajdos,

Fabrice Vandeput,

Eddie Yang,

Frank S. Menniti

Publication year - 2018

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.8b00374

Subject(s) - chemistry , quinazoline , phosphodiesterase , nucleotide , cyclic nucleotide phosphodiesterase , hydrolysis , cocrystal , combinatorial chemistry , biochemistry , enzyme , organic chemistry , molecule , gene , hydrogen bond

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.

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