Discovery of GS-9256: A novel phosphinic acid derived inhibitor of the hepatitis C virus NS3/4A protease with potent clinical activity

A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attr...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (3), p.1394-1396
Hauptverfasser:	Sheng, X. Christopher, Casarez, Anthony, Cai, Ruby, Clarke, Michael O., Chen, Xiaowu, Cho, Aesop, Delaney, William E., Doerffler, Edward, Ji, Mingzhe, Mertzman, Michael, Pakdaman, Rowchanak, Pyun, Hyung-Jung, Rowe, Tanisha, Wu, Qiaoyin, Xu, Jie, Kim, Choung U.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Carboxylate isostere Carrier Proteins - antagonists & inhibitors Chronic infection Clinical trials Dogs Drug Discovery Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology genotype Genotypes GS-9256 HCV Hepacivirus - drug effects Hepacivirus - enzymology Hepatitis C virus Humans Inhibitory Concentration 50 Medical sciences Molecular Structure NS3/4A protease inhibitor Peptides, Cyclic - chemical synthesis Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Pharmacokinetics Pharmacology. Drug treatments Phosphinic acid Phosphinic Acids - chemical synthesis Phosphinic Acids - chemistry Phosphinic Acids - pharmacology Proteinase proteinases quinoline Quinolines Swine Viral Nonstructural Proteins - antagonists & inhibitors
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Beschreibung
Zusammenfassung:	A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.12.038