Purpose: We investigated whether a clinically used carbonic anhydrase inhibitor (CAIs) can modulate intraocular pressure (IOP) through soluble adenylyl cyclase (sAC) signaling. Methods: IOP was measured 1 h after topical treatment with brinzolamide, a topically applied and clinically used CAIs, using direct cannulation of the anterior chamber in sAC knockout (KO) mice or C57BL/6J mice in the presence or absence of the sAC inhibitor (TDI-10229). Results: Mice treated with the sAC inhibitor TDI-10229 had elevated IOP. CAIs treatment significantly decreased increased intraocular pressure (IOP) in wild-type, sAC KO mice, as well as TDI-10229-treated mice. Conclusions: Inhibiting carbonic anhydrase reduces IOP independently from sAC in mice. Our studies suggest that the signaling cascade by which brinzolamide regulates IOP does not involve sAC.

01 Sep 2021·Molecular Human ReproductionQ3 · MEDICINE

Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization

Q3 · MEDICINE

Article

Author: Ghanem, Lubna ; Rossetti, Thomas ; Kaur, Navpreet ; Ritagliati, Carla ; Levin, Lonny R ; Krapf, Dario ; Fushimi, Makoto ; Wachten, Dagmar ; Santi, Celia Maria ; Hansen, Jan Niklas ; Buck, Jochen ; Ferreira, Jacob ; Balbach, Melanie ; Meinke, Peter T ; Puga Molina, Lis C

AbstractSoluble adenylyl cyclase (sAC: ADCY10) has been genetically confirmed to be essential for male fertility in mice and humans. In mice, ex vivo studies of dormant, caudal epididymal sperm demonstrated that sAC is required for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in mouse and human sperm. In contrast to caudal epididymal mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. In addition to preventing the capacitation-induced stimulation of sAC and protein kinase A activities, tyrosine phosphorylation, alkalinization, beat frequency and acrosome reaction in dormant mouse sperm, sAC inhibitors interrupt each of these capacitation-induced changes in ejaculated human sperm. Furthermore, we show for the first time that sAC is required during acrosomal exocytosis in mouse and human sperm. These data define sAC inhibitors as candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in women.

12 Aug 2021·ACS Medicinal Chemistry LettersQ3 · MEDICINE

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

Q3 · MEDICINE

Article

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

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Contraception	Discovery	US	Tri-Institutional Therapeutics Discovery Institute, Inc.	-

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