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

Autor:	Schenkel LB; 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., Olivieri PR; 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., Boezio AA; 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., Deak HL; 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., Emkey R; 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., Graceffa RF; 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., Gunaydin H; 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., Guzman-Perez A; 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., Lee JH; 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., Teffera Y; 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., Wang W; 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., Youngblood BD; 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., Yu VL; 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., Zhang M; 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., Gavva NR; 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., Lehto SG; 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., Geuns-Meyer S; 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.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 Mar 24; Vol. 59 (6), pp. 2794-809. Date of Electronic Publication: 2016 Mar 04.
DOI:	10.1021/acs.jmedchem.6b00039
Abstrakt:	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.
Databáze:	MEDLINE
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