Preclinical and clinical evaluation of a novel TRPA1 antagonist LY3526318

• Published in: Pain (Amsterdam) Vol. 166; no. 8; pp. 1893 - 1908
• Main Authors: Broad, Lisa M., Suico, Jeffrey G., Turner, P. Kellie, Nie, Si, Johnson, Kirk W., Sanger, Helen E., Wegiel, Lindsay A., Sperry, David C., Remick, David, Moran, Magdalene, Malekiani, Sam, del Camino, Donato, Wu, Xinyuan, Chong, Jayhong A., Blair, Nathaniel T., Wilke, August V.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Wolters Kluwer 01.08.2025
• Subjects: Adult; Analgesics - pharmacokinetics; Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Freund's Adjuvant - toxicity; Ganglia, Spinal - drug effects; HEK293 Cells; Humans; Hyperalgesia - drug therapy; Male; Pain - drug therapy; Pain Measurement - drug effects; Rats; Rats, Sprague-Dawley; TRPA1 Cation Channel - antagonists & inhibitors; TRPA1 Cation Channel - metabolism; TRPA1; Chronic pain
• ISSN: 0304-3959; 1872-6623; 1872-6623
• DOI: 10.1097/j.pain.0000000000003570

Supplemental Digital Content is Available in the Text.The transient receptor potential cation channel member A1 antagonist LY3526318 inhibited behavioral signs of enhanced nociception in animal models and was safe and well tolerated in phase 1 clinical studies. AbstractThe transient receptor potential cation channel member A1 (TRPA1) is heavily implicated in nociceptive signaling in both physiological and pathological pain states. However, it has been challenging to develop TRPA1 antagonists with appropriate properties to advance into clinical development. Herein, we describe the preclinical characterization and early clinical development of LY3526318, a potent, selective, and orally bioavailable TRPA1 antagonist. In vitro studies showed that LY3526318 reversibly inhibited recombinant TRPA1 channels with nanomolar potency that was conserved across species. LY3526318 also inhibited the function of native human and rat TRPA1 channels, including nociceptive dorsal root ganglion neuronal TRPA1 channels. In vivo studies showed that LY3526318 blocked formalin-evoked flinching behaviors and chronic Freund adjuvant-induced cold hypersensitivity in rats. Only male rats were used in these studies. Initial phase 1, single- and multiple-ascending dose studies evaluating pharmacokinetic and safety parameters of LY3526318 revealed a suboptimal pharmacokinetic profile leading to the development and study of a spray-dried dispersion (SDD) formulation of LY3526318. When dosed once daily at 250 mg, LY3526318-SDD showed a tmax of 4 hours and t1/2 of 12 hours, maintaining plasma exposures demonstrated to engage the TRPA1 target. Adverse events were transient and mild across all phase 1 studies. In summary, LY3526318 blocked TRPA1 in vitro and in vivo, inhibited behavioral signs of enhanced nociception in animal models, and was safe and well tolerated in phase 1 clinical studies, with LY3526318-SDD displaying an appropriate pharmacokinetic profile to advance to proof-of-concept studies in patients with chronic pain.