1区 · 医学
Article
作者: Beno, Brett R. ; Yeung, Kap-Sun ; Ng, Alicia ; Soars, Matthew G. ; Wang, Ying-Kai ; Bender, John A. ; Gao, Min ; Santone, Kenneth ; Shu, Yue-Zhong ; Sinz, Michael ; Mosure, Kathy ; Bora, Rajesh Onkardas ; Kadow, John F. ; Wan, Changhong ; Roberts, Susan B. ; Witmer, Mark ; Liu, Mengping ; Meanwell, Nicholas A. ; Grant-Young, Katherine A. ; Kish, Kevin ; Hanumegowda, Umesh ; Haskell, Roy ; Anjanappa, Prakash ; Colston, Elizabeth ; Nickel, Andrew ; Grasela, Dennis M. ; Parcella, Kyle ; Sheriff, Steven ; Gao, Qi ; Zhuo, Xiaoliang ; Selvakumar, Kumaravel ; Parker, Dawn ; Knipe, Jay O. ; Rigat, Karen ; Raybon, Joseph ; Gunaga, Prashantha ; Lemm, Julie
The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.
