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Papers of the Week

Papers: 5 Mar 2022 - 11 Mar 2022

2022 Mar 10

J Med Chem

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


Scott JA, Soto-Velasquez M, Hayes MP, LaVigne JE, Miller HR, Kaur J, Ejendal KFK, Watts VJ, Flaherty DP
J Med Chem. 2022 Mar 10.
PMID: 35271288.


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 AC8. Structure-activity relationship (SAR) studies led to analogues with cellular IC values as low as 0.25 μM, selectivity 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 Ca/calmodulin-stimulated AC1 activity to date with improved drug-like physicochemical properties making them potential lead compounds for the treatment of inflammatory pain.