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

  • ACS Med Chem Lett. 2017 Jun 29;8(7):771-774. doi: 10.1021/acsmedchemlett.7b00211.
Kyle Parcella  1 ,  Kyle Eastman  1 ,  Kap-Sun Yeung  1 ,  Katharine A Grant-Young  1 ,  Juliang Zhu  1 ,  Tao Wang  1 ,  Zhongxing Zhang  1 ,  Zhiwei Yin  1 ,  Dawn Parker  1 ,  Kathy Mosure  1 ,  Hua Fang  1 ,  Ying-Kai Wang  1 ,  Julie Lemm  1 ,  Xiaoliang Zhuo  1 ,  Umesh Hanumegowda  1 ,  Mengping Liu  1 ,  Karen Rigat  1 ,  Maria Donoso  1 ,  Maria Tuttle  1 ,  Tatyana Zvyaga  1 ,  Zuzana Haarhoff  1 ,  Nicholas A Meanwell  1 ,  Matthew G Soars  1 ,  Susan B Roberts  1 ,  John F Kadow  1
Affiliations
  • 1. Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
PMID: 28740615 DOI: 10.1021/acsmedchemlett.7b00211
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.

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