title: P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile.
abstract: 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.
authors.affiliation: Chemical Research, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. latha.nair@spcorp.com
authors.forename: Latha G
authors.initials: LG
authors.lastname: Nair
authors.forename: Mousumi
authors.initials: M
authors.lastname: Sannigrahi
authors.forename: Stephane
authors.initials: S
authors.lastname: Bogen
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Prongay
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.forename: K-C
authors.initials: KC
authors.lastname: Cheng
authors.forename: Viyyoor
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: F
authors.initials: F
authors.lastname: George Njoroge
mesh_terms: 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
chemical_list: 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