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

Kyle Parcella; Kyle Eastman; Kap-Sun Yeung; Katharine A Grant-Young; Juliang Zhu; Tao Wang; Zhongxing Zhang; Zhiwei Yin; Dawn Parker; Kathy Mosure; Hua Fang; Ying-Kai Wang; Julie Lemm; Xiaoliang Zhuo; Umesh Hanumegowda; Mengping Liu; Karen Rigat; Maria Donoso; Maria Tuttle; Tatyana Zvyaga; Zuzana Haarhoff; Nicholas A Meanwell; Matthew G Soars; Susan B Roberts; John F Kadow

doi:10.1021/acsmedchemlett.7b00211

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. eCollection 2017 Jul 13.

Authors

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

Affiliation

¹ Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.

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.