학술논문
Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.
Document Type
Article
Author
Kap-Sun Yeung; 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; Ying-Kai Wang; Mengping Liu; Lemm, Julie; Mosure, Kathy; Sheriff, Steven; Changhong Wan; Witmer, Mark; Kish, Kevin; Hanumegowda, Umesh
Source
Subject
*HEPATITIS C virus
*HEPATITIS C treatment
*ALLOSTERIC enzymes
*BENZOFURANS
*BENZOTHIAZINE
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Language
ISSN
0022-2623
Abstract
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. [ABSTRACT FROM AUTHOR]