title: Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease.
abstract: A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. michael_rudd@merck.com
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Romano
authors.forename: John W
authors.initials: JW
authors.lastname: Butcher
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bush
authors.forename: Charles J
authors.initials: CJ
authors.lastname: McIntyre
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gilbert
authors.forename: Terry A
authors.initials: TA
authors.lastname: Lyle
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Bang-Lin
authors.initials: BL
authors.lastname: Wan
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.forename: Christine
authors.initials: C
authors.lastname: Burlein
authors.forename: Jillian M
authors.initials: JM
authors.lastname: DiMuzio
authors.forename: Adam
authors.initials: A
authors.lastname: Gates
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Graham
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Steven W
authors.initials: SW
authors.lastname: Ludmerer
authors.forename: Stephanie
authors.initials: S
authors.lastname: McClain
authors.forename: Carolyn
authors.initials: C
authors.lastname: McHale
authors.forename: Mark
authors.initials: M
authors.lastname: Stahlhut
authors.forename: Christine
authors.initials: C
authors.lastname: Fandozzi
authors.forename: Anne
authors.initials: A
authors.lastname: Taylor
authors.forename: Nicole
authors.initials: N
authors.lastname: Trainor
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003500:Cyclization; D005838:Genotype; D006207:Half-Life; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011804:Quinolines / Q000737:chemistry; 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: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011804:Quinolines; D017361:Viral Nonstructural 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; C037219:quinoline