P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile.
SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1.
Nair
Latha G
LG
Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. latha.nair@spcorp.com
Sannigrahi
Mousumi
M
Bogen
Stephane
S
Pinto
Patrick
P
Chen
Kevin X
KX
Prongay
Andrew
A
Tong
Xiao
X
Cheng
K-C
KC
Girijavallabhan
Viyyoor
V
George Njoroge
F
F
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural 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; D007769:Lactams; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide