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

Laurie B Schenkel; Philip R Olivieri; Alessandro A Boezio; Holly L Deak; Renee Emkey; Russell F Graceffa; Hakan Gunaydin; Angel Guzman-Perez; Josie H Lee; Yohannes Teffera; Weiya Wang; Beth D Youngblood; Violeta L Yu; Maosheng Zhang; Narender R Gavva; Sonya G Lehto; Stephanie Geuns-Meyer

doi:10.1021/acs.jmedchem.6b00039

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. Epub 2016 Mar 4.

Authors

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

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.

MeSH terms

Animals
Biological Transport, Active
CHO Cells
Calcium Channels
Cricetulus
Dogs
Dose-Response Relationship, Drug
Drug Discovery
High-Throughput Screening Assays
Humans
In Vitro Techniques
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
Purines / chemical synthesis*
Purines / pharmacology*
Quinazolines / chemical synthesis*
Quinazolines / pharmacology*
Rats
Structure-Activity Relationship
TRPA1 Cation Channel
Transient Receptor Potential Channels / antagonists & inhibitors*

Substances

AM-0902
Calcium Channels
Nerve Tissue Proteins
Oxadiazoles
Purines
Quinazolines
TRPA1 Cation Channel
TRPA1 protein, human
Transient Receptor Potential Channels