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Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors.
Bagal, Sharan K; Omoto, Kiyoyuki; Blakemore, David C; Bungay, Peter J; Bilsland, James G; Clarke, Philip J; Corbett, Matthew S; Cronin, Ciaran N; Cui, J Jean; Dias, Rebecca; Flanagan, Neil J; Greasley, Samantha E; Grimley, Rachel; Johnson, Eric; Fengas, David; Kitching, Linda; Kraus, Michelle L; McAlpine, Indrawan; Nagata, Asako; Waldron, Gareth J; Warmus, Joseph S.
Afiliação
  • Bagal SK; Worldwide Medicinal Chemistry , Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Omoto K; Worldwide Medicinal Chemistry , Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Blakemore DC; Worldwide Medicinal Chemistry , Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Bungay PJ; Pharmacokinetics, Dynamics & Metabolism , Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Bilsland JG; Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Clarke PJ; Peakdale Molecular , Discovery Park House, Ramsgate Road , Sandwich , Kent CT13 9ND , U.K.
  • Corbett MS; Pfizer Global R&D, Groton Laboratories , Eastern Point Road , Groton , Connecticut 06340 , United States.
  • Cronin CN; Pfizer Global R&D, La Jolla Laboratories , 10770 Science Center Drive, San Diego , California 92121 , United States.
  • Cui JJ; Pfizer Global R&D, La Jolla Laboratories , 10770 Science Center Drive, San Diego , California 92121 , United States.
  • Dias R; Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Flanagan NJ; Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Greasley SE; Pfizer Global R&D, La Jolla Laboratories , 10770 Science Center Drive, San Diego , California 92121 , United States.
  • Grimley R; Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Johnson E; Pfizer Global R&D, La Jolla Laboratories , 10770 Science Center Drive, San Diego , California 92121 , United States.
  • Fengas D; Peakdale Molecular , Discovery Park House, Ramsgate Road , Sandwich , Kent CT13 9ND , U.K.
  • Kitching L; Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Kraus ML; Pfizer Global R&D, La Jolla Laboratories , 10770 Science Center Drive, San Diego , California 92121 , United States.
  • McAlpine I; Pfizer Global R&D, La Jolla Laboratories , 10770 Science Center Drive, San Diego , California 92121 , United States.
  • Nagata A; Pfizer Global R&D, La Jolla Laboratories , 10770 Science Center Drive, San Diego , California 92121 , United States.
  • Waldron GJ; Pfizer Global R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • Warmus JS; Pfizer Global R&D, Groton Laboratories , Eastern Point Road , Groton , Connecticut 06340 , United States.
J Med Chem ; 62(1): 247-265, 2019 01 10.
Article em En | MEDLINE | ID: mdl-29672039
ABSTRACT
Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor trkA / Inibidores de Proteínas Quinases Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor trkA / Inibidores de Proteínas Quinases Limite: Animals / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article