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Pubmed ID :28430437
Publication Date : //

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


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.

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

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