Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity

• Published in: Journal of medicinal chemistry Vol. 59; no. 6; pp. 2794 - 2809
• Main Authors: Schenkel, Laurie B, Olivieri, Philip R, Boezio, Alessandro A, Deak, Holly L, Emkey, Renee, Graceffa, Russell F, Gunaydin, Hakan, Guzman-Perez, Angel, Lee, Josie H, Teffera, Yohannes, Wang, Weiya, Youngblood, Beth D, Yu, Violeta L, Zhang, Maosheng, Gavva, Narender R, Lehto, Sonya G, Geuns-Meyer, Stephanie
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.03.2016; Amer Chemical Soc
• Subjects: Animals; Biological Transport, Active; Calcium Channels; Chemistry, Medicinal; CHO Cells; Cricetulus; Dogs; Dose-Response Relationship, Drug; Drug Discovery; High-Throughput Screening Assays; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Madin Darby Canine Kidney Cells; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Models, Molecular; Nerve Tissue Proteins - antagonists & inhibitors; Oxadiazoles - chemical synthesis; Oxadiazoles - pharmacology; Pain Measurement - drug effects; Pharmacology & Pharmacy; Purines - chemical synthesis; Purines - pharmacology; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; Transient Receptor Potential Channels - antagonists & inhibitors; TRPA1 Cation Channel; CHANNEL; ACTIVATE; PAIN
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00039

There has been significant interest in developing a transient receptor potential A1 (TRPA1) antagonist for the treatment of pain due to a wealth of data implicating its role in pain pathways. Despite this, identification of a potent small molecule tool possessing pharmacokinetic properties allowing for robust in vivo target coverage has been challenging. Here we describe the optimization of a potent, selective series of quinazolinone-based TRPA1 antagonists. High-throughput screening identified 4, which possessed promising potency and selectivity. A strategy focused on optimizing potency while increasing polarity in order to improve intrinisic clearance culminated with the discovery of purinone 27 (AM-0902), which is a potent, selective antagonist of TRPA1 with pharmacokinetic properties allowing for >30-fold coverage of the rat TRPA1 IC50 in vivo. Compound 27 demonstrated dose-dependent inhibition of AITC-induced flinching in rats, validating its utility as a tool for interrogating the role of TRPA1 in in vivo pain models.