Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors.
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.
Boloor
Amogh
A
Phenomix Corporation, 5930 Cornerstone Court West, Suite 230, San Diego, CA 92121, USA.
Hanway
Denise
D
Joshi
Maria
M
Winn
David T
DT
Mendez
Gabriel
G
Walls
Marlena
M
Wei
Ping
P
Qian
Fuxin
F
Zhang
Xiaoli
X
Zhang
Yuliang
Y
Hepperle
Michael E
ME
Li
Xinqiang
X
Campbell
David A
DA
Betancort
Juan M
JM
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001897:Boronic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D001897:Boronic Acids; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus