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

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.