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Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile.
Wilson, Kenneth J; Xiao, Jingbo; Chen, Catherine Z; Huang, Zaohua; Agoulnik, Irina U; Ferrer, Marc; Southall, Noel; Hu, Xin; Zheng, Wei; Xu, Xin; Wang, Amy; Myhr, Courtney; Barnaeva, Elena; George, Emmett R; Agoulnik, Alexander I; Marugan, Juan J.
Afiliação
  • Wilson KJ; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Xiao J; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Chen CZ; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Huang Z; Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, HLSI 419B, Miami, FL, 33199, USA.
  • Agoulnik IU; Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, HLSI 419B, Miami, FL, 33199, USA.
  • Ferrer M; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Southall N; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Hu X; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Zheng W; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Xu X; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Wang A; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Myhr C; Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, HLSI 419B, Miami, FL, 33199, USA.
  • Barnaeva E; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • George ER; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
  • Agoulnik AI; Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, HLSI 419B, Miami, FL, 33199, USA.
  • Marugan JJ; NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA. Electronic address: maruganj@mail.nih.gov.
Eur J Med Chem ; 156: 79-92, 2018 Aug 05.
Article em En | MEDLINE | ID: mdl-30006176
A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzamidas / Receptores de Peptídeos / Receptores Acoplados a Proteínas G / Células Estreladas do Fígado / Transcriptoma Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzamidas / Receptores de Peptídeos / Receptores Acoplados a Proteínas G / Células Estreladas do Fígado / Transcriptoma Idioma: En Ano de publicação: 2018 Tipo de documento: Article