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Discovery of BAY-390, a Selective CNS Penetrant Chemical Probe as Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonist.
Mesch, Stefanie; Walter, Daryl; Laux-Biehlmann, Alexis; Basting, Daniel; Flanagan, Stuart; Miyatake Ondozabal, Hideki; Bäurle, Stefan; Pearson, Christopher; Jenkins, James; Elves, Philip; Hess, Stephen; Coelho, Anne-Marie; Rotgeri, Andrea; Bothe, Ulrich; Nawaz, Schanila; Zollner, Thomas M; Steinmeyer, Andreas.
Afiliación
  • Mesch S; Pharmaceutical R&D, Drug Discovery, Medicinal Chemistry, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany.
  • Walter D; Discovery Chemistry, Evotec UK, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Laux-Biehlmann A; Exploratory Pathobiology, RED preMED, R&D, Bayer AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
  • Basting D; Pharmaceutical R&D, Drug Discovery, Lead Identification and Characterization, Bayer AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
  • Flanagan S; Discovery Chemistry, Evotec UK, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Miyatake Ondozabal H; Pharmaceutical R&D, Drug Discovery, Medicinal Chemistry, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany.
  • Bäurle S; Pharmaceutical R&D, Drug Discovery, Medicinal Chemistry, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany.
  • Pearson C; Discovery Chemistry, Evotec UK, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Jenkins J; Discovery Chemistry, Evotec UK, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Elves P; Discovery Chemistry, Evotec UK, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
  • Hess S; In Vitro Pharmacology, Evotec SE, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
  • Coelho AM; In Vivo Pharmacology, Evotec SE, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
  • Rotgeri A; Pharmaceutical R&D, Early Development, Drug Metabolism and Pharmacokinetics, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany.
  • Bothe U; Pharmaceutical R&D, Drug Discovery, Medicinal Chemistry, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany.
  • Nawaz S; In Vivo Pharmacology, Evotec SE, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
  • Zollner TM; Pharmaceutical R&D, Preclinical Research, Therapeutic Area Endocrinology, Metabolism and Reproductive Health, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany.
  • Steinmeyer A; Pharmaceutical R&D, Drug Discovery, Medicinal Chemistry, Bayer AG, Müllerstr. 178, 13353 Berlin, Germany.
J Med Chem ; 66(2): 1583-1600, 2023 01 26.
Article en En | MEDLINE | ID: mdl-36622903
Transient receptor potential ankyrin 1 (TRPA1) is a voltage-dependent, ligand-gated ion channel, and activation thereof is linked to a variety of painful conditions. Preclinical studies have demonstrated the role of TRPA1 receptors in a broad range of animal models of acute, inflammatory, and neuropathic pain. In addition, a clinical study using the TRPA1 antagonist GRC-17536 (Glenmark Pharmaceuticals) demonstrated efficacy in a subgroup of patients with painful diabetic neuropathy. Consequently, there is an increasing interest in TRPA1 inhibitors as potential analgesics. Herein, we report the identification of a fragment-like hit from a high-throughput screening (HTS) campaign and subsequent optimization to provide a novel and brain-penetrant TRPA1 inhibitor (compound 18, BAY-390), which is now being made available to the research community as an open-source in vivo probe.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Canales de Potencial de Receptor Transitorio / Neuralgia Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Canales de Potencial de Receptor Transitorio / Neuralgia Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos