Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates

Abstract

Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization. Pharmacologic evaluation of existing sAC inhibitors for utility as on-demand, nonhormonal male contraceptives suggested that both high intrinsic potency, fast on and slow dissociation rates are essential design elements for successful male contraceptive applications. During the course of the medicinal chemistry campaign described here, we identified sAC inhibitors that fulfill these criteria and are suitable for in vivo evaluation of diverse sAC pharmacology.

On-demand male contraception via acute inhibition of soluble adenylyl cyclase

“…1d ). TDI-11861 is highly specific for sAC; it had no activity against tmACs from each subfamily 37 .

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“…However, in addition to exploiting the bicarbonate binding site engaged by LRE1 and TDI-10229, TDI-11861 also occupies a channel leading to the active site (Fig. 1b ) 35 , 37 . Thus, TDI-11861 binds sAC protein tighter and inhibits the in vitro adenylyl cyclase activity of purified sAC protein with an improved IC 50 of 3 nM (Fig.…”

“…Like its predecessor TDI-10229 20 , 36 , in addition to being specific for sAC versus related tmACs, sAC showed an overall benign safety profile, both in vitro and in vivo 37 . TDI-11861 had no significant activity (1) versus a 46-member safety panel comprised of ion channels, GPCRs, kinases, and nuclear receptors; (2) against over 310 kinases; (3) in hERG electrophysiology studies; (4) in glutathione trapping assays; (5) in AMES assays and DEREK analysis for mutagenicity risks; nor (6) cytotoxicity in cell viability assays at 20 µM, which is >2000 fold above its IC 50 .…”

“…Inhibition with the previously used tool compound TDI-10229 did not survive dilution into inhibitor-free media (i.e., the sAC-inhibitor complex dissociated rapidly, releasing active enzyme) 20 , consistent with TDI-10229 having a short residence time on sAC protein 38 . Our structure-assisted drug design efforts identified a more potent sAC inhibitor with longer residence time and drug-like properties suitable for use in vivo to interrogate functions of sAC in animal models 37 . TDI-11861 (Fig.…”

Structure-Kinetic Relationship for Drug Design Revealed by PLS Model with Retrosynthesis-Based Pre-trained Molecular Representation and Molecular Dynamics Simulation

“…The copyright holder for this preprint this version posted November 29, 2022. ; https://doi.org/10.1101/2022.11.28.518282 doi: bioRxiv preprint Miller et al found a novel compound TDI-11861 which shows both improved sAC (ADCY10) binding affinity and residence time than its precursor (3181 s versus to 25 s). 61 Combining induced fit docking and MM/GBSA calculation cubic by cubic, Bai et al, construct a sophisticated energy landscape of ligand dissociation and found a potential lead compound which shows better binding kinetic and thermodynamic properties with either TcAChE or mAChE. 62 Here, we combine ML, accelerated MD and similarity search to find potential molecules with longer retention time than their precursors.…”