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

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

doi:10.1021/acs.jmedchem.8b00374

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

Journal Article · Wed May 02 04:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b00374· OSTI ID:1499732

^[1]; Movsesian, Matthew ^[2]; ^[1]; Becker, Stacey L. ^[1]; Chappie, Thomas A. ^[3]; Jenkinson, Stephen ^[4]; Liras, Jennifer L. ^[3]; Liras, Spiros ^[3]; Orozco, Christine ^[1]; Pandit, Jayvardhan ^[1]; Vajdos, Felix F. ^[1]; Vandeput, Fabrice ^[2]; Yang, Eddie ^[1]; Menniti, Frank S. ^[5]

Pfizer World Wide Research and Development, Groton, CT (United States)
Univ. of Utah School of Medicine, Salt Lake City, UT (United States)
Pfizer Worldwide Research and Development, Cambridge, MA (United States)
Pfizer World Wide Research and Development, La Jolla, CA (United States)
MindImmune Therapeutics, Inc., Kingston, RI (United States); Univ. of Rhode Island, Kingston, RI (United States). George & Anne Ryan Inst. for Neuroscience

Herein 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor; US Department of Veterans Affairs (VA); Eunice Kennedy Shriver National Institute for Child Health & Human Development (NICHD)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1499732

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 10 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (16)

Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart Miller, Clint L.; Cai, Yujun; Oikawa, Masayoshi Basic Research in Cardiology, Vol. 106, Issue 6 https://doi.org/10.1007/s00395-011-0228-2	journal	October 2011
Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective Bobin, Pierre; Belacel-Ouari, Milia; Bedioune, Ibrahim Archives of Cardiovascular Diseases, Vol. 109, Issue 6-7 https://doi.org/10.1016/j.acvd.2016.02.004	journal	June 2016
Discovery of Potent and Selective Inhibitors of Phosphodiesterase 1 for the Treatment of Cognitive Impairment Associated with Neurodegenerative and Neuropsychiatric Diseases Li, Peng; Zheng, Hailin; Zhao, Jun Journal of Medicinal Chemistry, Vol. 59, Issue 3 https://doi.org/10.1021/acs.jmedchem.5b01751	journal	February 2016
Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties Dyck, Brian; Branstetter, Bryan; Gharbaoui, Tawfik Journal of Medicinal Chemistry, Vol. 60, Issue 8 https://doi.org/10.1021/acs.jmedchem.7b00302	journal	April 2017
Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes Wager, Travis T.; Chandrasekaran, Ramalakshmi Y.; Hou, Xinjun ACS Chemical Neuroscience, Vol. 1, Issue 6 https://doi.org/10.1021/cn100007x	journal	March 2010
Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties Wager, Travis T.; Hou, Xinjun; Verhoest, Patrick R. ACS Chemical Neuroscience, Vol. 1, Issue 6 https://doi.org/10.1021/cn100008c	journal	March 2010
New Methods of Synthesis of β-Aminoethylpyrazoles Jones, Reuben G.; Mann, Marjorie J. Journal of the American Chemical Society, Vol. 75, Issue 16 https://doi.org/10.1021/ja01112a050	journal	August 1953
Reactions of Hydrazines with γ-Pyrones Ainsworth, Cameron; Jones, Reuben G. Journal of the American Chemical Society, Vol. 76, Issue 12 https://doi.org/10.1021/ja01641a018	journal	June 1954
Small-molecule phosphodiesterase probes: discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1 Humphrey, John M.; Yang, Eddie; Ende, Christopher W. am Med. Chem. Commun., Vol. 5, Issue 9 https://doi.org/10.1039/C4MD00113C	journal	January 2014
Phosphodiesterase 1 regulation is a key mechanism in vascular aging Niño, Paula K. Bautista; Durik, Matej; Danser, A. H. Jan Clinical Science, Vol. 129, Issue 12 https://doi.org/10.1042/CS20140753	journal	October 2015
PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction Knight, Walter E.; Chen, Si; Zhang, Yishuai Proceedings of the National Academy of Sciences, Vol. 113, Issue 45 https://doi.org/10.1073/pnas.1607728113	journal	October 2016
Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A Soderling, S. H.; Bayuga, S. J.; Beavo, J. A. Proceedings of the National Academy of Sciences, Vol. 96, Issue 12 https://doi.org/10.1073/pnas.96.12.7071	journal	June 1999
Cyclic Nucleotide Phosphodiesterase PDE1C1 in Human Cardiac Myocytes Vandeput, Fabrice; Wolda, Sharon L.; Krall, Judith Journal of Biological Chemistry, Vol. 282, Issue 45 https://doi.org/10.1074/jbc.M703173200	journal	November 2007
Role of Ca ²⁺ /Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase 1 in Mediating Cardiomyocyte Hypertrophy Miller, Clint L.; Oikawa, Masayoshi; Cai, Yujun Circulation Research, Vol. 105, Issue 10 https://doi.org/10.1161/CIRCRESAHA.109.198515	journal	November 2009
Role of cAMP-Phosphodiesterase 1C Signaling in Regulating Growth Factor Receptor Stability, Vascular Smooth Muscle Cell Growth, Migration, and Neointimal Hyperplasia Cai, Yujun; Nagel, David J.; Zhou, Qian Circulation Research, Vol. 116, Issue 7 https://doi.org/10.1161/CIRCRESAHA.116.304408	journal	March 2015
Immunohistochemical Localization of Phosphodiesterase 10A in Multiple Mammalian Species Coskran, Timothy M.; Morton, Daniel; Menniti, Frank S. Journal of Histochemistry & Cytochemistry, Vol. 54, Issue 11 https://doi.org/10.1369/jhc.6A6930.2006	journal	July 2006

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An EPAC1/PDE1C-Signaling Axis Regulates Formation of Leading-Edge Protrusion in Polarized Human Arterial Vascular Smooth Muscle Cells Brzezinska, Paulina; Maurice, Donald H. Cells, Vol. 8, Issue 12 https://doi.org/10.3390/cells8121473	journal	November 2019

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

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