First-in-Class Dual Hybrid Carbonic Anhydrase Inhibitors and Transient Receptor Potential Vanilloid 1 Agonists Revert Oxaliplatin-Induced Neuropathy

Abstract

Here, we report for the first time a series of compounds potentially useful for the management of oxaliplatin-induced neuropathy (OINP) able to modulate the human Carbonic Anhydrases (hCAs) as well as the Transient Receptor Potential Vanilloid 1 (TRPV1). All compounds showed effective in vitro inhibition activity toward the main hCAs involved in such a pathology, whereas selected items reported moderate agonism of TRPV1. X-ray crystallographic experiments assessed the binding modes of the two enantiomers (R)-37a and (S)-37b within the hCA II cleft. Although the tails assumed diverse orientations, no appreciable effects were observed for their hCA II affinity. Similarly, the activity of (R)-39a and (S)-39b on TRPV1 was not influenced by the stereocenters. In vivo evaluation of the most promising derivatives (R)-12a, (R)-37a, and the two enantiomers (R)-39a, (S)-39b revealed antihypersensitivity effects in a mouse model of OINP with potent and persistent effect up to 75 min after administration.