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Discovery of Ervogastat (PF-06865571): A Potent and Selective Inhibitor of Diacylglycerol Acyltransferase 2 for the Treatment of Non-alcoholic Steatohepatitis.
Futatsugi, Kentaro; Cabral, Shawn; Kung, Daniel W; Huard, Kim; Lee, Esther; Boehm, Markus; Bauman, Jonathan; Clark, Ronald W; Coffey, Steven B; Crowley, Collin; Dechert-Schmitt, Anne-Marie; Dowling, Matthew S; Dullea, Robert; Gosset, James R; Kalgutkar, Amit S; Kou, Kou; Li, Qifang; Lian, Yajing; Loria, Paula M; Londregan, Allyn T; Niosi, Mark; Orozco, Christine; Pettersen, John C; Pfefferkorn, Jeffrey A; Polivkova, Jana; Ross, Trenton T; Sharma, Raman; Stock, Ingrid A; Tesz, Gregory; Wisniewska, Hanna; Goodwin, Bryan; Price, David A.
Afiliación
  • Futatsugi K; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Cabral S; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Kung DW; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Huard K; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Lee E; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Boehm M; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Bauman J; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Clark RW; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Coffey SB; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Crowley C; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Dechert-Schmitt AM; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Dowling MS; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Dullea R; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Gosset JR; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Kalgutkar AS; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Kou K; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Li Q; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Lian Y; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Loria PM; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Londregan AT; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Niosi M; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Orozco C; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Pettersen JC; Pfizer Inc. Drug Safety R&D, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Pfefferkorn JA; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Polivkova J; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Ross TT; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Sharma R; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Stock IA; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Tesz G; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Wisniewska H; Pfizer Inc. Medicine Design, Eastern Point Road, Groton, Connecticut 06340, United States.
  • Goodwin B; Pfizer Inc. Internal Medicine Research Unit, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • Price DA; Pfizer Inc. Medicine Design, 1 Portland Street, Cambridge, Massachusetts 02139, United States.
J Med Chem ; 65(22): 15000-15013, 2022 11 24.
Article en En | MEDLINE | ID: mdl-36322383
Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diacilglicerol O-Acetiltransferasa / Enfermedad del Hígado Graso no Alcohólico Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diacilglicerol O-Acetiltransferasa / Enfermedad del Hígado Graso no Alcohólico Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos