P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl alpha-ketoamide based HCV protease inhibitors.
With the aim of discovering potent and selective HCV protease inhibitors, we synthesized and evaluated a series of 1a based tetrapeptidyl ketoamides with additional modification(s) at P1', P1, and P3 positions. As a result of this effort, we found that replacement of the P3 valine with tert-leucine resulted in the discovery of a series of inhibitors (e.g., 3a, 3c, and 4c) endowed with improved enzyme and/or cellular activity relative to 1a. When dosed to F-344 rats orally at 50mg/kg, 3a achieved 2.5x higher liver and plasma exposure in comparison to that detected with 1a.
Victor
Frantz
F
Lilly Research Laboratory, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Lamar
Jason
J
Snyder
Nancy
N
Yip
Yvonne
Y
Guo
Deqi
D
Yumibe
Nathan
N
Johnson
Robert B
RB
Wang
Q May
QM
Glass
John I
JI
Chen
Shu-Hui
SH
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D008297:Male; D011392:Proline / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D001643:Bridged Bicyclo Compounds; D011392:Proline; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases