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Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent in Vivo Activity.
Schenkel, Laurie B; Olivieri, Philip R; Boezio, Alessandro A; Deak, Holly L; Emkey, Renee; Graceffa, Russell F; Gunaydin, Hakan; Guzman-Perez, Angel; Lee, Josie H; Teffera, Yohannes; Wang, Weiya; Youngblood, Beth D; Yu, Violeta L; Zhang, Maosheng; Gavva, Narender R; Lehto, Sonya G; Geuns-Meyer, Stephanie.
Afiliación
  • 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.
  • Olivieri PR; 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.
  • Deak HL; 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.
  • Graceffa RF; 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.
  • Guzman-Perez A; 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.
  • Teffera Y; 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.
  • Youngblood BD; 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.
  • Zhang M; 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.
  • Lehto SG; 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.
J Med Chem ; 59(6): 2794-809, 2016 Mar 24.
Article en En | MEDLINE | ID: mdl-26942860
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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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Oxadiazoles / Purinas / Quinazolinas / Canales de Potencial de Receptor Transitorio / Proteínas del Tejido Nervioso Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Oxadiazoles / Purinas / Quinazolinas / Canales de Potencial de Receptor Transitorio / Proteínas del Tejido Nervioso Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos