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The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation.
Regueiro-Ren, Alicia; Sit, Sing-Yuen; Chen, Yan; Chen, Jie; Swidorski, Jacob J; Liu, Zheng; Venables, Brian L; Sin, Ny; Hartz, Richard A; Protack, Tricia; Lin, Zeyu; Zhang, Sharon; Li, Zhufang; Wu, Dauh-Rurng; Li, Peng; Kempson, James; Hou, Xiaoping; Gupta, Anuradha; Rampulla, Richard; Mathur, Arvind; Park, Hyunsoo; Sarjeant, Amy; Benitex, Yulia; Rahematpura, Sandhya; Parker, Dawn; Phillips, Thomas; Haskell, Roy; Jenkins, Susan; Santone, Kenneth S; Cockett, Mark; Hanumegowda, Umesh; Dicker, Ira; Meanwell, Nicholas A; Krystal, Mark.
Afiliación
  • Regueiro-Ren A; Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey08543, United States.
  • Sit SY; Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Chen Y; Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Chen J; Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Swidorski JJ; Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Liu Z; Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Venables BL; Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Sin N; Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Hartz RA; Department of Discovery Chemistry, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Protack T; Department of Virology, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Lin Z; Department of Virology, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Zhang S; Department of Virology, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Li Z; Department of Virology, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Wu DR; Department of Discovery Synthesis, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey08543, United States.
  • Li P; Department of Discovery Synthesis, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey08543, United States.
  • Kempson J; Department of Discovery Synthesis, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey08543, United States.
  • Hou X; Department of Discovery Synthesis, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey08543, United States.
  • Gupta A; Department of Discovery Synthesis; Bristol Myers Squibb Research and Early Development, Bangalore 560099, India.
  • Rampulla R; Department of Discovery Synthesis, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey08543, United States.
  • Mathur A; Department of Discovery Synthesis, Bristol Myers Squibb Research and Early Development, PO Box 4000, Princeton, New Jersey08543, United States.
  • Park H; Bristol Myers Squibb Chemical and Synthetic Development, New Brunswick, New Jersey08901, United States.
  • Sarjeant A; Bristol Myers Squibb Chemical and Synthetic Development, New Brunswick, New Jersey08901, United States.
  • Benitex Y; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Rahematpura S; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Parker D; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Phillips T; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Haskell R; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Jenkins S; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Santone KS; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Cockett M; Department of Virology, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Hanumegowda U; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Dicker I; Department of Virology, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
  • Meanwell NA; Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, Princeton, New Jersey08543, United States.
  • Krystal M; Department of Virology, Bristol Myers Squibb Research and Early Development, 5 Research Parkway, Wallingford, Connecticut06492, United States.
J Med Chem ; 65(18): 11927-11948, 2022 09 22.
Article en En | MEDLINE | ID: mdl-36044257
ABSTRACT
GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH2F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triterpenos / VIH-1 / Fármacos Anti-VIH Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triterpenos / VIH-1 / Fármacos Anti-VIH Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos