دورية أكاديمية
Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity.
| العنوان: | Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity. |
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| المؤلفون: | 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. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2016 Mar 24; Vol. 59 (6), pp. 2794-809. Date of Electronic Publication: 2016 Mar 04. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Nerve Tissue Proteins/*antagonists & inhibitors , Oxadiazoles/*chemical synthesis , Oxadiazoles/*pharmacology , Purines/*chemical synthesis , Purines/*pharmacology , Quinazolines/*chemical synthesis , Quinazolines/*pharmacology , Transient Receptor Potential Channels/*antagonists & inhibitors, 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 ; Pain Measurement/drug effects ; Rats ; Structure-Activity Relationship ; TRPA1 Cation Channel |
| مستخلص: | 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. |
| المشرفين على المادة: | 0 (AM-0902) 0 (Calcium Channels) 0 (Nerve Tissue Proteins) 0 (Oxadiazoles) 0 (Purines) 0 (Quinazolines) 0 (TRPA1 Cation Channel) 0 (TRPA1 protein, human) 0 (Transient Receptor Potential Channels) |
| تواريخ الأحداث: | Date Created: 20160305 Date Completed: 20160823 Latest Revision: 20171116 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1021/acs.jmedchem.6b00039 |
| PMID: | 26942860 |
| قاعدة البيانات: | MEDLINE |
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