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Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.
Sun, Li-Qiang; Mull, Eric; Zheng, Barbara; D'Andrea, Stanley; Zhao, Qian; Wang, Alan Xiangdong; Sin, Ny; Venables, Brian L; Sit, Sing-Yuen; Chen, Yan; Chen, Jie; Cocuzza, Anthony; Bilder, Donna M; Mathur, Arvind; Rampulla, Richard; Chen, Bang-Chi; Palani, Theerthagiri; Ganesan, Sivakumar; Arunachalam, Pirama Nayagam; Falk, Paul; Levine, Steven; Chen, Chaoqun; Friborg, Jacques; Yu, Fei; Hernandez, Dennis; Sheaffer, Amy K; Knipe, Jay O; Han, Yong-Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael W; Zvyaga, Tatyana; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E; Gao, Qi; Ng, Alicia; Mueller, Luciano; Grasela, Dennis M; Adams, Stephen; Loy, James; Levesque, Paul C; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, William; Li, Danshi; Zhu, Jialong.
Afiliación
  • Mathur A; Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.
  • Rampulla R; Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.
  • Chen BC; Department of Discovery Synthesis, Bristol-Myers Squibb Research and Development , Route 206 and Provinceline Road, Princeton, New Jersey 08543, United States.
  • Palani T; Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Ganesan S; Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Arunachalam PN; Biocon Bristol-Myers Squibb R&D Center , Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Gao Q; Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.
  • Ng A; Department of Pharmaceutical Development, Bristol-Myers Squibb Research and Development , 1 Squibb Drive, New Brunswick, New Jersey 08903, United States.
  • Adams S; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
  • Levesque PC; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
  • Sun H; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
  • Shi H; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
  • Sun L; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
  • Warner W; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
  • Li D; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
  • Zhu J; Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development , 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, United States.
J Med Chem ; 59(17): 8042-60, 2016 09 08.
Article en En | MEDLINE | ID: mdl-27564532
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Oligopéptidos / Sulfonamidas / Proteínas no Estructurales Virales / Hepacivirus / Isoquinolinas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Oligopéptidos / Sulfonamidas / Proteínas no Estructurales Virales / Hepacivirus / Isoquinolinas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2016 Tipo del documento: Article Pais de publicación: Estados Unidos