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Publication Abstract from PubMed

Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.,Miller M, Rossetti T, Ferreira J, Ghanem L, Balbach M, Kaur N, Levin LR, Buck J, Kehr M, Coquille S, van den Heuvel J, Steegborn C, Fushimi M, Finkin-Groner E, Myers RW, Kargman S, Liverton NJ, Huggins DJ, Meinke PT J Med Chem. 2022 Nov 24;65(22):15208-15226. doi: 10.1021/acs.jmedchem.2c01133. , Epub 2022 Nov 8. PMID:36346696^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.