Discovery of the new active ingredient tigolaner, an allosteric modulator of the GABA-gated chloride channel for use as a spot-on ectoparasiticide in animal health.

Parasiticides play a crucial role in animal health. The need for innovative ectoparasiticides for companion animals has been growing, driven by the risks posed by parasites to both animals and humans. We detail here the discovery pathway of tigolaner, an ectoparasiticide, offering up to 13 weeks protection against fleas and ticks to cats. Felpreva® employs this active ingredient for ectoparasite control together with the endoparasiticides emodepside and praziquantel. It was approved by the European Medicines Agency in November 2021. The discovery of tigolaner resulted from research at Bayer focused on finding novel molecules inhibiting GABA-gated chloride channels (GABA-Cls), with an improved toxicological profile and resistance-breaking potential when compared to dieldrin and fipronil. A high-throughput in vitro screening campaign on GABA-Cls, followed by a "mix-match" synthetic approach, led to the identification of several lead compounds acting as allosteric modulators. The GABA lead class compounds showed a different binding site when compared to fipronil. They have a unique chemotype based on a pyrazole moiety. Further variations of the central ring led to the discovery of tigolaner. Selected structure-activity relationships from the project are presented. Some synthetic pathways for tigolaner and its analogs are also described. This publication also outlines the efficacy of tigolaner against various parasites, making it a key compound of the Felpreva® product.