Literature DB >> 28740615

Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor.

Kyle Parcella1, Kyle Eastman1, Kap-Sun Yeung1, Katharine A Grant-Young1, Juliang Zhu1, Tao Wang1, Zhongxing Zhang1, Zhiwei Yin1, Dawn Parker1, Kathy Mosure1, Hua Fang1, Ying-Kai Wang1, Julie Lemm1, Xiaoliang Zhuo1, Umesh Hanumegowda1, Mengping Liu1, Karen Rigat1, Maria Donoso1, Maria Tuttle1, Tatyana Zvyaga1, Zuzana Haarhoff1, Nicholas A Meanwell1, Matthew G Soars1, Susan B Roberts1, John F Kadow1.   

Abstract

Iterative structure-activity analyses in a class of highly functionalized furo[2,3-b]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (14), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (14) is described.

Entities:  

Keywords:  Hepatitis C virus; NS5B polymerase; azabenzofuran; deuterium; metabolic stability; primer grip

Year:  2017        PMID： 28740615      PMCID： PMC5512134          DOI： 10.1021/acsmedchemlett.7b00211

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  10 in total

1.  Hepatitis C virus genotypes and quasispecies.

Authors:  G L Davis
Journal:  Am J Med       Date:  1999-12-27       Impact factor: 4.965

2.  Heavy drugs draw heavy interest from pharma backers.

Authors:  Alla Katsnelson
Journal:  Nat Med       Date:  2013-06       Impact factor: 53.440

3.  Hepatitis C virus genotype 7, a new genotype originating from central Africa.

Authors:  Donald G Murphy; Erwin Sablon; Jasmine Chamberland; Eric Fournier; Raymond Dandavino; Cécile L Tremblay
Journal:  J Clin Microbiol       Date:  2014-12-17       Impact factor: 5.948

4.  Global burden of hepatitis C: considerations for healthcare providers in the United States.

Authors:  Francisco M Averhoff; Nancy Glass; Deborah Holtzman
Journal:  Clin Infect Dis       Date:  2012-07       Impact factor: 9.079

5.  Using deuterium in drug discovery: leaving the label in the drug.

Authors:  Thomas G Gant
Journal:  J Med Chem       Date:  2013-12-02       Impact factor: 7.446

6.  Chronic Hepatitis C Virus Infection: A Review of Current Direct-Acting Antiviral Treatment Strategies.

Authors:  Johnathan Zhang; Douglas Nguyen; Ke-Qin Hu
Journal:  N Am J Med Sci (Boston)       Date:  2016-04-27

7.  Discovery and initial optimization of alkoxyanthranilic acid derivatives as inhibitors of HCV NS5B polymerase.

Authors:  Kyle Parcella; Andrew Nickel; Brett R Beno; Steven Sheriff; Changhong Wan; Ying-Kai Wang; Susan B Roberts; Nicholas A Meanwell; John F Kadow
Journal:  Bioorg Med Chem Lett       Date:  2016-11-22       Impact factor: 2.823

8.  Determining hepatitis C genotype by analyzing the sequence of the NS5b region.

Authors:  K Sandres-Sauné; P Deny; C Pasquier; V Thibaut; G Duverlie; J Izopet
Journal:  J Virol Methods       Date:  2003-05       Impact factor: 2.014

Review 9.  Nucleoside, nucleotide, and non-nucleoside inhibitors of hepatitis C virus NS5B RNA-dependent RNA-polymerase.

Authors:  Michael J Sofia; Wonsuk Chang; Phillip A Furman; Ralph T Mosley; Bruce S Ross
Journal:  J Med Chem       Date:  2012-01-23       Impact factor: 7.446

10.  Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.

Authors:  Kap-Sun Yeung; Brett R Beno; Kyle Parcella; John A Bender; Katherine A Grant-Young; Andrew Nickel; Prashantha Gunaga; Prakash Anjanappa; Rajesh Onkardas Bora; Kumaravel Selvakumar; Karen Rigat; Ying-Kai Wang; Mengping Liu; Julie Lemm; Kathy Mosure; Steven Sheriff; Changhong Wan; Mark Witmer; Kevin Kish; Umesh Hanumegowda; Xiaoliang Zhuo; Yue-Zhong Shu; Dawn Parker; Roy Haskell; Alicia Ng; Qi Gao; Elizabeth Colston; Joseph Raybon; Dennis M Grasela; Kenneth Santone; Min Gao; Nicholas A Meanwell; Michael Sinz; Matthew G Soars; Jay O Knipe; Susan B Roberts; John F Kadow
Journal:  J Med Chem       Date:  2017-05-04       Impact factor: 7.446
  10 in total
  1 in total

1.  Hydro/Deutero Deamination of Arylazo Sulfones under Metal- and (Photo)Catalyst-Free Conditions.

Authors:  Hawraz I M Amin; Carlotta Raviola; Ahmed A Amin; Barbara Mannucci; Stefano Protti; Maurizio Fagnoni
Journal:  Molecules       Date:  2019-06-08       Impact factor: 4.411
  1 in total

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