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

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.

SUBMITTER: Fushimi M

PROVIDER: S-EPMC8366019 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Fushimi Makoto M Buck Hannes H Balbach Melanie M Gorovyy Anna A Ferreira Jacob J Rossetti Thomas T Kaur Navpreet N Levin Lonny R LR Buck Jochen J Quast Jonathan J van den Heuvel Joop J Steegborn Clemens C Finkin-Groner Efrat E Kargman Stacia S Michino Mayako M Foley Michael A MA Miller Michael M Liverton Nigel J NJ Huggins David J DJ Meinke Peter T PT

ACS medicinal chemistry letters 20210714 8

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 <i>in vivo</i> interrogation of sAC inhibition to assess its potential therapeutic applications. This work culminated in the identification of TDI-10229 (<b>12</b>), which displays nanomolar inhibition of sAC in both biochemical and cellular assays and exhibits mouse pharmacoki ...[more]

PMID: 34413957

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