Literature DB >> 34413957

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

Makoto Fushimi1, Hannes Buck2, Melanie Balbach2, Anna Gorovyy2, Jacob Ferreira2, Thomas Rossetti2, Navpreet Kaur2, Lonny R Levin2, Jochen Buck2, Jonathan Quast3, Joop van den Heuvel4, Clemens Steegborn3, Efrat Finkin-Groner1, Stacia Kargman1, Mayako Michino1, Michael A Foley1, Michael Miller1, Nigel J Liverton1, David J Huggins1,5, Peter T Meinke1,2.   

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.
© 2021 American Chemical Society.

Entities:  

Year:  2021        PMID： 34413957      PMCID： PMC8366019          DOI： 10.1021/acsmedchemlett.1c00273

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.632


  13 in total

1.  The "soluble" adenylyl cyclase in sperm mediates multiple signaling events required for fertilization.

Authors:  Kenneth C Hess; Brian H Jones; Becky Marquez; Yanqiu Chen; Teri S Ord; Margarita Kamenetsky; Catarina Miyamoto; Jonathan H Zippin; Gregory S Kopf; Susan S Suarez; Lonny R Levin; Carmen J Williams; Jochen Buck; Stuart B Moss
Journal:  Dev Cell       Date:  2005-08       Impact factor: 12.270

2.  Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field.

Authors:  Lingle Wang; Yujie Wu; Yuqing Deng; Byungchan Kim; Levi Pierce; Goran Krilov; Dmitry Lupyan; Shaughnessy Robinson; Markus K Dahlgren; Jeremy Greenwood; Donna L Romero; Craig Masse; Jennifer L Knight; Thomas Steinbrecher; Thijs Beuming; Wolfgang Damm; Ed Harder; Woody Sherman; Mark Brewer; Ron Wester; Mark Murcko; Leah Frye; Ramy Farid; Teng Lin; David L Mobley; William L Jorgensen; Bruce J Berne; Richard A Friesner; Robert Abel
Journal:  J Am Chem Soc       Date:  2015-02-12       Impact factor: 15.419

Review 3.  Pharmacological modulation of the CO2/HCO3-/pH-, calcium-, and ATP-sensing soluble adenylyl cyclase.

Authors:  Shakarr V Wiggins; Clemens Steegborn; Lonny R Levin; Jochen Buck
Journal:  Pharmacol Ther       Date:  2018-05-26       Impact factor: 12.310

4.  Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect.

Authors:  Gloria Esposito; Bijay S Jaiswal; Fang Xie; Magda A M Krajnc-Franken; Tamara J A A Robben; Ankie M Strik; Cor Kuil; Ria L A Philipsen; Marcel van Duin; Marco Conti; Jan A Gossen; Byjay S Jaiswal
Journal:  Proc Natl Acad Sci U S A       Date:  2004-02-19       Impact factor: 11.205

5.  Using In Silico Tools in a Weight of Evidence Approach to Aid Toxicological Assessment.

Authors:  Claire M Ellison; Judith C Madden; Philip Judson; Mark T D Cronin
Journal:  Mol Inform       Date:  2010-01-12       Impact factor: 3.353

Review 6.  Bicarbonate, carbon dioxide and pH sensing via mammalian bicarbonate-regulated soluble adenylyl cyclase.

Authors:  Tom Rossetti; Stephanie Jackvony; Jochen Buck; Lonny R Levin
Journal:  Interface Focus       Date:  2021-02-12       Impact factor: 3.906

7.  High-Throughput Quantitative Intrinsic Thiol Reactivity Evaluation Using a Fluorescence-Based Competitive Endpoint Assay.

Authors:  Tomoya Sameshima; Ikuo Miyahisa; Seiji Yamasaki; Mika Gotou; Toshitake Kobayashi; Junichi Sakamoto
Journal:  SLAS Discov       Date:  2017-04-20       Impact factor: 3.341

8.  Crystal structure of human soluble adenylate cyclase reveals a distinct, highly flexible allosteric bicarbonate binding pocket.

Authors:  Susanne M Saalau-Bethell; Valerio Berdini; Anne Cleasby; Miles Congreve; Joseph E Coyle; Victoria Lock; Christopher W Murray; M Alistair O'Brien; Sharna J Rich; Tracey Sambrook; Mladen Vinkovic; Jeff R Yon; Harren Jhoti
Journal:  ChemMedChem       Date:  2014-02-24       Impact factor: 3.466

9.  Optimization of lead compounds into on-demand, non-hormonal contraceptives: leveraging a public-private drug discovery institute collaboration.

Authors:  Melanie Balbach; Makoto Fushimi; David J Huggins; Clemens Steegborn; Peter T Meinke; Lonny R Levin; Jochen Buck
Journal:  Biol Reprod       Date:  2020-04-20       Impact factor: 4.285

10.  Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase.

Authors:  Lavoisier Ramos-Espiritu; Silke Kleinboelting; Felipe A Navarrete; Antonio Alvau; Pablo E Visconti; Federica Valsecchi; Anatoly Starkov; Giovanni Manfredi; Hannes Buck; Carolina Adura; Jonathan H Zippin; Joop van den Heuvel; J Fraser Glickman; Clemens Steegborn; Lonny R Levin; Jochen Buck
Journal:  Nat Chem Biol       Date:  2016-08-22       Impact factor: 15.040
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  3 in total

1.  Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization.

Authors:  Melanie Balbach; Lubna Ghanem; Thomas Rossetti; Navpreet Kaur; Carla Ritagliati; Jacob Ferreira; Dario Krapf; Lis C Puga Molina; Celia Maria Santi; Jan Niklas Hansen; Dagmar Wachten; Makoto Fushimi; Peter T Meinke; Jochen Buck; Lonny R Levin
Journal:  Mol Hum Reprod       Date:  2021-09-01       Impact factor: 4.518

2.  Strategies to safely target widely expressed soluble adenylyl cyclase for contraception.

Authors:  Jacob Ferreira; Lonny R Levin; Jochen Buck
Journal:  Front Pharmacol       Date:  2022-08-25       Impact factor: 5.988

3.  Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential.

Authors:  Thomas Rossetti; Jacob Ferreira; Lubna Ghanem; Hannes Buck; Clemens Steegborn; Robert W Myers; Peter T Meinke; Lonny R Levin; Jochen Buck
Journal:  Front Physiol       Date:  2022-09-28       Impact factor: 4.755
  3 in total

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