TDI-11861

TDI-11861 is an inhibitor of soluble adenylyl cyclase (sAC; IC₅₀ = 3.3 nM), a bicarbonate-regulated cytosolic enzyme also known as AC10.¹ It is selective for sAC over the transmembrane ACs (tmACs) AC1, AC2, AC5, AC8, and AC9 at 100 nM, a panel of 322 kinases (IC₅₀s = >1,000 nM for all), and 46 other targets, including G protein-coupled receptors (GPCRs), nuclear receptors, and ion channels, with 50% response concentration values (RC₅₀s) of greater than 9 µM. TDI-11861 has an increased residence time when binding to sAC in a surface plasmon resonance (SPR) assay and a slower dissociation rate in a jump dilution recovery assay compared with the sAC inhibitor TDI-10229 (Item No. 37674), indicating a lower risk of post-copulation female genital tract dilution. It inhibits capacitation-induced cAMP accumulation in isolated mouse and human sperm when used at a concentration of 5 µM and reduces sodium bicarbonate-induced increases in mouse and human sperm beat frequency.² Oral administration of a single dose of TDI-11861 (50 mg/kg) induces temporary infertility in male mice without affecting mating behavior.

WARNING This product is not for human or veterinary use.

1. Miller, M., Rossetti, T., Ferreira, J., et al. Design, synthesis, and pharmacological evaluation of second-generation soluble adenylyl cyclase (sAC, ADCY10) inhibitors with slow dissociation rates. J. Med. Chem. 65(22), 15208-15226 (2022).

2. Balbach, M., Rossetti, T., Ferreira, J., et al. On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nat. Commun. 14(1), 637 (2023).