Inhibitors of hepatitis C virus NS3/4A: alpha-ketoamide based macrocyclic inhibitors.
A novel series of hepatitis C virus (HCV) NS3/4A protease inhibitors bearing a P2-P4 macrocycle and a P1-P1' alpha-ketoamide serine trap is reported. The NS3 protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. The optimization of both the macrocycle and the warhead portions led to the discovery of compounds 8b and 8 g with a good activity both in the enzyme as well as in the cell based (replicon) assays with favorable PK profile in a preclinical species.
Avolio
Salvatore
S
IRBM-Merck Research Laboratories Rome, Pomezia, Rome, Italy. salvatore_avolio@merck.com
Robertson
Keith
K
Hernando
Josè Ignacio Martin
JI
DiMuzio
Jillian
J
Summa
Vincenzo
V
D000577:Amides / Q000138:chemical synthesis; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D047908:Intracellular Signaling Peptides and Proteins; D007659:Ketones / Q000138:chemical synthesis; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D008297:Male; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000577:Amides; D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007659:Ketones; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D015842:Serine Proteinase 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