Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.
Yeung, K.S., Beno, B.R., Parcella, K., Bender, J.A., Grant-Young, K.A., Nickel, A., Gunaga, P., Anjanappa, P., Bora, R.O., Selvakumar, K., Rigat, K., Wang, Y.K., Liu, M., Lemm, J., Mosure, K., Sheriff, S., Wan, C., Witmer, M., Kish, K., Hanumegowda, U., Zhuo, X., Shu, Y.Z., Parker, D., Haskell, R., Ng, A., Gao, Q., Colston, E., Raybon, J., Grasela, D.M., Santone, K., Gao, M., Meanwell, N.A., Sinz, M., Soars, M.G., Knipe, J.O., Roberts, S.B., Kadow, J.F.(2017) J Med Chem 60: 4369-4385
- PubMed: 28430437
- DOI: https://doi.org/10.1021/acs.jmedchem.7b00328
- Primary Citation of Related Structures:
5PZK, 5PZL, 5PZM, 5PZN, 5PZO, 5PZP - PubMed 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.
Organizational Affiliation:
Bristol-Myers Squibb Research and Development , P.O. Box 5100, 5 Research Parkway, Wallingford, Connecticut 06492, United States.