title: Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers.
abstract: A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.
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: Charles J
authors.initials: CJ
authors.lastname: McIntyre
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Romano
authors.forename: John W
authors.initials: JW
authors.lastname: Butcher
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bush
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: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.forename: Bang-Lin
authors.initials: BL
authors.lastname: Wan
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: Joseph P
authors.initials: JP
authors.lastname: Vacca
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: John A
authors.initials: JA
authors.lastname: McCauley
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain; 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; D062105:Molecular Docking Simulation; D009154:Mutation; 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: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047028:Macrocyclic Compounds; 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; C455041:NS4A cofactor peptide, Hepatitis C virus