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

  • Michael Miller
    Michael Miller
    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States
  • Thomas Rossetti
    Thomas Rossetti
    Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States
  • Jacob Ferreira
    Jacob Ferreira
    Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States
  • Lubna Ghanem
    Lubna Ghanem
    Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States
    More by Lubna Ghanem
  • Melanie Balbach
    Melanie Balbach
    Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States
  • Navpreet Kaur
    Navpreet Kaur
    Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States
  • Lonny R. Levin
    Lonny R. Levin
    Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States
  • Jochen Buck
    Jochen Buck
    Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States
    More by Jochen Buck
  • Maria Kehr
    Maria Kehr
    Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
    More by Maria Kehr
  • Sandrine Coquille
    Sandrine Coquille
    Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
  • Joop van den Heuvel
    Joop van den Heuvel
    Helmholtz Centre for Infection Research, Recombinant Protein Expression, Inhoffenstrasse 7, 38124 Braunschweig, Germany
  • Clemens Steegborn
    Clemens Steegborn
    Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany
  • Makoto Fushimi
    Makoto Fushimi
    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States
  • Efrat Finkin-Groner
    Efrat Finkin-Groner
    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States
  • Robert W. Myers
    Robert W. Myers
    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States
  • Stacia Kargman
    Stacia Kargman
    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States
  • Nigel J. Liverton
    Nigel J. Liverton
    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States
  • David J. Huggins*
    David J. Huggins
    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States
    Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10021, United States
    *Email: [email protected]. Phone: +1-646-962-6133. Website: www.tritdi.org.
  • , and 
  • Peter T. Meinke
    Peter T. Meinke
    Tri-Institutional Therapeutics Discovery Institute, New York, New York 10021, United States
    Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States
Cite this: J. Med. Chem. 2022, 65, 22, 15208–15226
Publication Date (Web):November 8, 2022
https://doi.org/10.1021/acs.jmedchem.2c01133
Copyright © 2022 American Chemical Society

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    Abstract

    Abstract Image

    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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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01133.

    • Inhibitory activities of TDI-11861 against human tmACs (Figure S1); HPLC traces for 2, 4, 9, 19, 20, 22, 23, 26, 28, and 33; synthesis and characterization for 5–14, 16–18, and 21–32; diffraction data and refinement statistics (Table S1); kinase activity data for TDI-11861 (33) (Table S2); drug target safety panel data for TDI-11861 (33) (Table S3); and analytical method for mouse plasma samples (PDF)

    • Smiles data (CSV)

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    Cited By

    This article is cited by 4 publications.

    1. Feng Zhou, Shiqiu Yin, Yi Xiao, Zaiyun Lin, Weiqiang Fu, Yingsheng J. Zhang. Structure–Kinetic Relationship for Drug Design Revealed by a PLS Model with Retrosynthesis-Based Pre-Trained Molecular Representation and Molecular Dynamics Simulation. ACS Omega 2023, 8 (20) , 18312-18322. https://doi.org/10.1021/acsomega.3c02294
    2. Shan Sun, Makoto Fushimi, Thomas Rossetti, Navpreet Kaur, Jacob Ferreira, Michael Miller, Jonathan Quast, Joop van den Heuvel, Clemens Steegborn, Lonny R. Levin, Jochen Buck, Robert W. Myers, Stacia Kargman, Nigel Liverton, Peter T. Meinke, David J. Huggins. Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation. Journal of Chemical Information and Modeling 2023, 63 (9) , 2828-2841. https://doi.org/10.1021/acs.jcim.2c01577
    3. Melanie Balbach, Thomas Rossetti, Jacob Ferreira, Lubna Ghanem, Carla Ritagliati, Robert W. Myers, David J. Huggins, Clemens Steegborn, Ileana C. Miranda, Peter T. Meinke, Jochen Buck, Lonny R. Levin. On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nature Communications 2023, 14 (1) https://doi.org/10.1038/s41467-023-36119-6
    4. Thomas Rossetti, Jacob Ferreira, Lubna Ghanem, Hannes Buck, Clemens Steegborn, Robert W. Myers, Peter T. Meinke, Lonny R. Levin, Jochen Buck. Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential. Frontiers in Physiology 2022, 13 https://doi.org/10.3389/fphys.2022.1013845

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