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

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.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1397305
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 10
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

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., and Kadow, John F. Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.7b00328.
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. Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies. United States. doi:10.1021/acs.jmedchem.7b00328.
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., and Kadow, John F. Thu . "Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies". United States. doi:10.1021/acs.jmedchem.7b00328.
@article{osti_1397305,
title = {Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies},
author = {Yeung, Kap-Sun and Beno, Brett R. and Parcella, Kyle and Bender, John A. and Grant-Young, Katherine A. and Nickel, Andrew and Gunaga, Prashantha and Anjanappa, Prakash and Bora, Rajesh Onkardas and Selvakumar, Kumaravel and Rigat, Karen and Wang, Ying-Kai and Liu, Mengping and Lemm, Julie and Mosure, Kathy and Sheriff, Steven and Wan, Changhong and Witmer, Mark and Kish, Kevin and Hanumegowda, Umesh and Zhuo, Xiaoliang and Shu, Yue-Zhong and Parker, Dawn and Haskell, Roy and Ng, Alicia and Gao, Qi and Colston, Elizabeth and Raybon, Joseph and Grasela, Dennis M. and Santone, Kenneth and Gao, Min and Meanwell, Nicholas A. and Sinz, Michael and Soars, Matthew G. and Knipe, Jay O. and Roberts, Susan B. and Kadow, John F.},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.7b00328},
journal = {Journal of Medicinal Chemistry},
number = 10,
volume = 60,
place = {United States},
year = {Thu May 04 00:00:00 EDT 2017},
month = {Thu May 04 00:00:00 EDT 2017}
}