| Literature DB >> 35271288 |
Jason A Scott1, Monica Soto-Velasquez1, Michael P Hayes1, Justin E LaVigne1, Heath R Miller1, Jatinder Kaur1, Karin F K Ejendal1, Val J Watts1,2,3, Daniel P Flaherty1,2,3.
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.Entities:
Mesh：
Substances：
Year: 2022 PMID： 35271288 PMCID： PMC9390083 DOI： 10.1021/acs.jmedchem.1c01759
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039