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7-Methylation of Chenodeoxycholic Acid Derivatives Yields a Substantial Increase in TGR5 Receptor Potency.
Nakhi, Ali; McDermott, Connor M; Stoltz, Kristen L; John, Kristen; Hawkinson, Jon E; Ambrose, Elizabeth A; Khoruts, Alexander; Sadowsky, Michael J; Dosa, Peter I.
Afiliación
  • Nakhi A; Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
  • McDermott CM; Department of Medicinal Chemistry , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
  • Stoltz KL; Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
  • John K; Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
  • Hawkinson JE; Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
  • Ambrose EA; Department of Medicinal Chemistry , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
  • Khoruts A; Center for Immunology, Department of Medicine, Division of Gastroenterology , University of Minnesota , Minneapolis , Minnesota 55414 , United States.
  • Sadowsky MJ; BioTechnology Institute, Department of Soil, Water & Climate, and Department of Plant and Microbial Biology , University of Minnesota , St. Paul , Minnesota 55108 , United States.
  • Dosa PI; BioTechnology Institute, Department of Soil, Water & Climate, and Department of Plant and Microbial Biology , University of Minnesota , St. Paul , Minnesota 55108 , United States.
J Med Chem ; 62(14): 6824-6830, 2019 07 25.
Article en En | MEDLINE | ID: mdl-31268316
ABSTRACT
TGR5 agonists are potential therapeutics for a variety of conditions including type 2 diabetes, obesity, and inflammatory bowel disease. After screening a library of chenodeoxycholic acid (CDCA) derivatives, it was determined that a range of modifications could be made to the acid moiety of CDCA which significantly increased TGR5 agonist potency. Surprisingly, methylation of the 7-hydroxyl of CDCA led to a further dramatic increase in potency, allowing the identification of 5.6 nM TGR5 agonist 17.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Ácido Quenodesoxicólico / Receptores Acoplados a Proteínas G Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Ácido Quenodesoxicólico / Receptores Acoplados a Proteínas G Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos