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

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

  • J Med Chem. 2016 Mar 24;59(6):2794-809. doi: 10.1021/acs.jmedchem.6b00039.
Laurie B Schenkel 1 2,  Philip R Olivieri 1 2,  Alessandro A Boezio 1 2,  Holly L Deak 1 2,  Renee Emkey 1 2,  Russell F Graceffa 1 2,  Hakan Gunaydin 1 2,  Angel Guzman-Perez 1 2,  Josie H Lee 1 2,  Yohannes Teffera 1 2,  Weiya Wang 1 2,  Beth D Youngblood 1 2,  Violeta L Yu 1 2,  Maosheng Zhang 1 2,  Narender R Gavva 1 2,  Sonya G Lehto 1 2,  Stephanie Geuns-Meyer 1 2
Affiliations

Affiliations

  • 1 Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 2 Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
PMID: 26942860 DOI: 10.1021/acs.jmedchem.6b00039
Abstract

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 intrinsic 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.

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