| Literature DB >> 27564532 |
Li-Qiang Sun, Eric Mull, Barbara Zheng, Stanley D'Andrea, Qian Zhao, Alan Xiangdong Wang, Ny Sin, Brian L Venables, Sing-Yuen Sit, Yan Chen, Jie Chen, Anthony Cocuzza, Donna M Bilder, Arvind Mathur1, Richard Rampulla1, Bang-Chi Chen1, Theerthagiri Palani2, Sivakumar Ganesan2, Pirama Nayagam Arunachalam2, Paul Falk, Steven Levine, Chaoqun Chen, Jacques Friborg, Fei Yu, Dennis Hernandez, Amy K Sheaffer, Jay O Knipe, Yong-Hae Han, Richard Schartman, Maria Donoso, Kathy Mosure, Michael W Sinz, Tatyana Zvyaga, Ramkumar Rajamani, Kevin Kish, Jeffrey Tredup, Herbert E Klei, Qi Gao3, Alicia Ng3, Luciano Mueller, Dennis M Grasela, Stephen Adams4, James Loy, Paul C Levesque4, Huabin Sun4, Hong Shi4, Lucy Sun4, William Warner4, Danshi Li4, Jialong Zhu4, Ying-Kai Wang, Hua Fang, Mark I Cockett, Nicholas A Meanwell, Fiona McPhee, Paul M Scola.
Abstract
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).Entities:
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Year: 2016 PMID： 27564532 DOI： 10.1021/acs.jmedchem.6b00821
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446