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.
Department of Medicinal Chemistry, Merck Research Labs, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Stephane.Bogen@spcorp.com
Stéphane L
SL
Bogen
Ashok
A
Arasappan
Francisco
F
Velazquez
Melissa
M
Blackman
Regina
R
Huelgas
Weidong
W
Pan
Elise
E
Siegel
Latha G
LG
Nair
Srikanth
S
Venkatraman
Zhuyan
Z
Guo
Ronald
R
Doll
Neng-Yang
NY
Shih
F George
FG
Njoroge
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