2. Academic Validation
  3. Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates

  • J Med Chem. 2022 Nov 8. doi: 10.1021/acs.jmedchem.2c01133.
Michael Miller 1,  Thomas Rossetti 2,  Jacob Ferreira 2,  Lubna Ghanem 2,  Melanie Balbach 2,  Navpreet Kaur 2,  Lonny R Levin 2,  Jochen Buck 2,  Maria Kehr 3,  Sandrine Coquille 3,  Joop van den Heuvel 4,  Clemens Steegborn 3,  Makoto Fushimi 1,  Efrat Finkin-Groner 1,  Robert W Myers 1,  Stacia Kargman 1,  Nigel J Liverton 1,  David J Huggins 1 5,  Peter T Meinke 1 2
Affiliations

Affiliations

  • 1 Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States.
  • 2 Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States.
  • 3 Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany.
  • 4 Helmholtz Centre for Infection Research, Recombinant Protein Expression, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
  • 5 Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10021, United States.
PMID: 36346696 DOI: 10.1021/acs.jmedchem.2c01133
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.

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