Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease

Authors: Terrett JA, Ly JQ, Katavolos P, Hasselgren C, Laing S, Zhong F, Villemure E, Déry M, Larouche-Gauthier R, Chen H, Shore DG, Lee WP, Suto E, Johnson K, Brooks M, Stablein A, Beaumier F, Constantineau-Forget L, Grand-Maître C, Lépissier L, Ciblat S, Sturino C, Chen Y, Hu B, Elstrott J, Gandham V, Joseph V, Booler H, Cain G, Chou C, Fullerton A, Lepherd M, Stainton S, Torres E, Urban K, Yu L, Zhong Y, Bao L, Chou KJ, Lin J, Zhang W, La H, Liu L, Mulder T, Chen J, Chernov-Rogan T, Johnson AR, Hackos DH, Leahey R, Shields SD, Balestrini A, Riol-Blanco L, Safina BS, Volgraf M, Magnuson S, Kakiuchi-Kiyota S
Publication: J Med Chem
Keywords: animal scaling, dose selection, fih, first-in-human, gastroplus, in vitro–in vivo extrapolation, IVIVE, PBPK modeling, physiologically based pharmacokinetics, translational science
Software: GastroPlus®

Abstract

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 metabolite─generated 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.

By Jack 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, and Satoko Kakiuchi-Kiyota