Discovery of potent sulfonamide P4-capped ketoamide second generation inhibitors of hepatitis C virus NS3 serine protease with favorable pharmacokinetic profiles in preclinical species.
Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.
Bogen
Stéphane L
SL
Department of Medicinal Chemistry, Merck Research Labs, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Stephane.Bogen@spcorp.com
Arasappan
Ashok
A
Velazquez
Francisco
F
Blackman
Melissa
M
Huelgas
Regina
R
Pan
Weidong
W
Siegel
Elise
E
Nair
Latha G
LG
Venkatraman
Srikanth
S
Guo
Zhuyan
Z
Doll
Ronald
R
Shih
Neng-Yang
NY
Njoroge
F George
FG
D000577:Amides / Q000737:chemistry*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D003198:Computer Simulation; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D029968:Escherichia coli Proteins; D000882:Haplorhini; D006801:Humans; D008565:Membrane Proteins; D008958:Models, Molecular; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000577:Amides; D000998:Antiviral Agents; D029968:Escherichia coli Proteins; D008565:Membrane Proteins; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D014508:Urea; D017361:Viral Nonstructural Proteins; C415989:CcmD protein, E coli; C549972:N-(5-cyclopropyl-1-(cyclopropylamino)-1,2-dioxopentan-3-yl)-3-(2-(3-(1-((N-cyclopropyl-N-methylsulfamoyl)methyl)cyclohexyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexane-2-carboxamide; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases