Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates
Michael Miller, Thomas Rossetti, Jacob Ferreira, Lubna Ghanem, Melanie Balbach, Navpreet Kaur, Lonny R. Levin, Jochen Buck, Maria Kehr, Sandrine Coquille, Joop van den Heuvel, Clemens Steegborn, Makoto Fushimi, Efrat Finkin-Groner, Robert W. Myers, Stacia Kargman, Nigel J. Liverton, David J. Huggins, Peter T. Meinke
Abstract
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.