Discovery of TRPA1
Antagonist GDC-6599: Derisking Preclinical Toxicity and
Aldehyde Oxidase Metabolism
with a Potential First-in-Class Therapy for Respiratory Disease
Version 2 2024-03-08, 18:43Version 2 2024-03-08, 18:43
Version 1 2024-03-03, 13:03Version 1 2024-03-03, 13:03
journal contribution
posted on 2024-03-08, 18:43authored byJack A. Terrett, Justin Q. Ly, Paula Katavolos, Catrin Hasselgren, Steven Laing, Fiona Zhong, Elisia Villemure, Martin Déry, Robin Larouche-Gauthier, Huifen Chen, Daniel G. Shore, Wyne P. Lee, Eric Suto, Kevin Johnson, Marjory Brooks, Alyssa Stablein, Francis Beaumier, Léa Constantineau-Forget, Chantal Grand-Maître, Luce Lépissier, Stéphane Ciblat, Claudio Sturino, Yong Chen, Baihua Hu, Justin Elstrott, Vineela Gandham, Victory Joseph, Helen Booler, Gary Cain, Carolina Chou, Aaron Fullerton, Michelle Lepherd, Shannon Stainton, Elizabeth Torres, Konnie Urban, Lanlan Yu, Yu Zhong, Linda Bao, Kang-Jye Chou, Jessica Lin, Wei Zhang, Hank La, Liling Liu, Teresa Mulder, Jun Chen, Tania Chernov-Rogan, Adam R. Johnson, David H. Hackos, Rebecca Leahey, Shannon D. Shields, Alessia Balestrini, Lorena Riol-Blanco, Brian S. Safina, Matthew Volgraf, Steven Magnuson, Satoko Kakiuchi-Kiyota
Transient
receptor potential ankyrin 1 (TRPA1) is a nonselective
calcium ion channel highly expressed in the primary sensory neurons,
functioning as a polymodal sensor for exogenous and endogenous stimuli,
and has been implicated in neuropathic pain and respiratory disease.
Herein, we describe the optimization of potent, selective, and orally
bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead
molecules in preclinical single- and short-term repeat-dose toxicity
studies exhibited profound prolongation of coagulation parameters.
Based on a thorough investigative toxicology and clinical pathology
analysis, anticoagulation effects in vivo are hypothesized
to be manifested by a metabolitegenerated by aldehyde oxidase
(AO)possessing a similar pharmacophore to known anticoagulants
(i.e., coumarins, indandiones). Further optimization to block AO-mediated
metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical
candidate GDC-6599, currently in Phase II clinical trials
for respiratory indications.