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)

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 ap...

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Veröffentlicht in:ACS medicinal chemistry letters 2021-08, Vol.12 (8), p.1283-1287
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.1c00273