title: Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity.
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.
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Schenkel
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Olivieri
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Boezio
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Holly L
authors.initials: HL
authors.lastname: Deak
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Renee
authors.initials: R
authors.lastname: Emkey
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Russell F
authors.initials: RF
authors.lastname: Graceffa
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Josie H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Teffera
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Beth D
authors.initials: BD
authors.lastname: Youngblood
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Violeta L
authors.initials: VL
authors.lastname: Yu
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.affiliation: Departments of Medicinal Chemistry, ‡Lead Discovery, §Molecular Structure, and ∥Pharmacokinetics and Drug Metabolism, Amgen, Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.|Neuroscience, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Geuns-Meyer
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D016466:CHO Cells; D015220:Calcium Channels; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D061985:Madin Darby Canine Kidney Cells; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors*
chemical_list: C000609916:AM-0902; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D010069:Oxadiazoles; D011687:Purines; D011799:Quinazolines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels