Title | Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | 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 |
Journal | J Med Chem |
Volume | 65 |
Issue | 22 |
Pagination | 15208-15226 |
Date Published | 2022 Nov 24 |
ISSN | 1520-4804 |
Keywords | Adenylyl Cyclases, Animals, Contraceptive Agents, Male, Male, Oocytes, Signal Transduction, Sperm Motility |
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. |
DOI | 10.1021/acs.jmedchem.2c01133 |
Alternate Journal | J Med Chem |
PubMed ID | 36346696 |
PubMed Central ID | PMC9866367 |
Grant List | P50 HD100549 / HD / NICHD NIH HHS / United States R01 AG061290 / AG / NIA NIH HHS / United States R21 EY025810 / EY / NEI NIH HHS / United States |