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Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.
Sun, Li-Qiang; Mull, Eric; D'Andrea, Stanley; Zheng, Barbara; Hiebert, Sheldon; Gillis, Eric; Bowsher, Michael; Kandhasamy, Sarkunam; Baratam, Venkata Rao; Puttaswamy, Sunitha; Pulicharla, Nagalakshmi; Vishwakrishnan, Sureshbabu; Reddy, Subba; Trivedi, Ravi; Sinha, Sarmistha; Sivaprasad, Sankar; Rao, Abhijith; Desai, Salil; Ghosh, Kaushik; Anumula, Rushith; Kumar, Amit; Rajamani, Ramkumar; Wang, Ying-Kai; Fang, Hua; Mathur, Arvind; Rampulla, Richard; Zvyaga, Tatyana A; Mosure, Kathy; Jenkins, Susan; Falk, Paul; Tagore, Debarati M; Chen, Chaoqun; Rendunchintala, Kishore; Loy, James; Meanwell, Nicholas A; McPhee, Fiona; Scola, Paul M.
Afiliação
  • Sun LQ; Bristol Myers Squibb Research and Early Development, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States.
  • Mull E; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • D'Andrea S; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Zheng B; Bristol Myers Squibb Research and Early Development, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States.
  • Hiebert S; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Gillis E; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Bowsher M; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Kandhasamy S; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Baratam VR; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Puttaswamy S; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Pulicharla N; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Vishwakrishnan S; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Reddy S; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Trivedi R; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Sinha S; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Sivaprasad S; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Rao A; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Desai S; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Ghosh K; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Anumula R; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Kumar A; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Rajamani R; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Wang YK; Bristol Myers Squibb Research and Early Development, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States.
  • Fang H; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Mathur A; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Rampulla R; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Zvyaga TA; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Mosure K; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Jenkins S; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Falk P; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Tagore DM; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Chen C; Bristol Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • Rendunchintala K; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
  • Loy J; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Meanwell NA; Bristol Myers Squibb Research and Early Development, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States.
  • McPhee F; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Scola PM; Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, Massachusetts 02142, United States.
J Med Chem ; 63(23): 14740-14760, 2020 12 10.
Article em En | MEDLINE | ID: mdl-33226226
ABSTRACT
The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Peptídeos Cíclicos / Inibidores de Serina Proteinase / Proteínas não Estruturais Virais Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Peptídeos Cíclicos / Inibidores de Serina Proteinase / Proteínas não Estruturais Virais Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos