Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

  • J Med Chem. 2022 Mar 24;65(6):4667-4686. doi: 10.1021/acs.jmedchem.1c01759.
Jason A Scott  1 ,  Monica Soto-Velasquez  1 ,  Michael P Hayes  1 ,  Justin E LaVigne  1 ,  Heath R Miller  1 ,  Jatinder Kaur  1 ,  Karin F K Ejendal  1 ,  Val J Watts  1  2  3 ,  Daniel P Flaherty  1  2  3
Affiliations
  • 1. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2. Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States.
  • 3. Purdue Institute for Integrative Neuroscience, 207 South Martin Jischke Dr. West Lafayette, Indiana 47907, United States.
PMID: 35271288 DOI: 10.1021/acs.jmedchem.1c01759
Abstract

Adenylyl cyclase type 1 (AC1) is involved in signaling for chronic pain sensitization in the central nervous system and is an emerging target for the treatment of chronic pain. AC1 and a closely related isoform AC8 are also implicated to have roles in learning and memory signaling processes. Our team has carried out cellular screening for inhibitors of AC1 yielding a pyrazolyl-pyrimidinone scaffold with low micromolar potency against AC1 and selectivity versus AC8. Structure-activity relationship (SAR) studies led to analogues with cellular IC50 values as low as 0.25 μM, selectivity versus AC8 and Other AC isoforms as well as Other common neurological targets. A representative analogue displayed modest antiallodynic effects in a mouse model of inflammatory pain. This series represents the most potent and selective inhibitors of CA2+/calmodulin-stimulated AC1 activity to date with improved drug-like physicochemical properties making them potential lead compounds for the treatment of inflammatory pain.

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