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

Fushimi, Makoto; Buck, Hannes; Balbach, Melanie; Gorovyy, Anna; Ferreira, Jacob; Rossetti, Thomas; Kaur, Navpreet; Levin, Lonny R.; Buck, Jochen; Quast, Jonathan; van den Heuvel, Joop; Steegborn, Clemens; Finkin-Groner, Efrat; Kargman, Stacia; Michino, Mayako; Foley, Michael A.; Miller, Michael; Liverton, Nigel J.; Huggins, David J.; Meinke, Peter T.

doi:10.1021/acsmedchemlett.1c00273.s001

ml1c00273_si_001.pdf (2.62 MB)

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

Version 2 2021-07-20, 19:07

Version 1 2021-07-14, 17:12

journal contribution

posted on 2021-07-20, 19:07 authored by Makoto Fushimi, Hannes Buck, Melanie Balbach, Anna Gorovyy, Jacob Ferreira, Thomas Rossetti, Navpreet Kaur, Lonny R. Levin, Jochen Buck, Jonathan Quast, Joop van den Heuvel, Clemens Steegborn, Efrat Finkin-Groner, Stacia Kargman, Mayako Michino, Michael A. Foley, Michael Miller, Nigel J. Liverton, David J. Huggins, Peter T. Meinke

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.