2. Academic Validation
  3. Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10)

Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10)

  • ACS Med Chem Lett. 2021 Jul 14;12(8):1283-1287. doi: 10.1021/acsmedchemlett.1c00273.
Makoto Fushimi 1,  Hannes Buck 2,  Melanie Balbach 2,  Anna Gorovyy 2,  Jacob Ferreira 2,  Thomas Rossetti 2,  Navpreet Kaur 2,  Lonny R Levin 2,  Jochen Buck 2,  Jonathan Quast 3,  Joop van den Heuvel 4,  Clemens Steegborn 3,  Efrat Finkin-Groner 1,  Stacia Kargman 1,  Mayako Michino 1,  Michael A Foley 1,  Michael Miller 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-Zentrum für Infektionsforschung, 38124 Braunschweig, Germany.
  • 5 Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10021, United States.
PMID: 34413957 DOI: 10.1021/acsmedchemlett.1c00273
Abstract

Soluble adenylyl cyclase (sAC) has gained attention as a potential therapeutic target given the role of this Enzyme in intracellular signaling. We describe successful efforts to design improved sAC inhibitors amenable for in vivo interrogation of sAC inhibition to assess its potential therapeutic applications. This work culminated in the identification of TDI-10229 (12), which displays nanomolar inhibition of sAC in both biochemical and cellular assays and exhibits mouse pharmacokinetic properties sufficient to warrant its use as an in vivo tool compound.

Figures
Products