Open AccessDiscovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10)
Author(s) -
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
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00273
Subject(s) - adenylyl cyclase , in vivo , adcy9 , adcy10 , pharmacology , intracellular , chemistry , enzyme , bioavailability , pharmacokinetics , biochemistry , biology , microbiology and biotechnology
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.