title: P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: discovery of MK-2748 and MK-6325.
abstract: With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA (USA). michael_rudd@merck.com.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.forename: John W
authors.initials: JW
authors.lastname: Butcher
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Charles J
authors.initials: CJ
authors.lastname: McIntyre
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Romano
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gilbert
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Bush
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: Steven
authors.initials: S
authors.lastname: Harper
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrara
authors.forename: Marcello
authors.initials: M
authors.lastname: DiFilippo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
authors.forename: John
authors.initials: J
authors.lastname: Swestock
authors.forename: Jeff
authors.initials: J
authors.lastname: Fritzen
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: Stephanie
authors.initials: S
authors.lastname: McClain
authors.forename: Carolyn
authors.initials: C
authors.lastname: McHale
authors.forename: Mark W
authors.initials: MW
authors.lastname: Stahlhut
authors.forename: Stuart
authors.initials: S
authors.lastname: Black
authors.forename: Robert
authors.initials: R
authors.lastname: Chase
authors.forename: Aileen
authors.initials: A
authors.lastname: Soriano
authors.forename: Christine M
authors.initials: CM
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: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.forename: Steven W
authors.initials: SW
authors.lastname: Ludmerer
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008958:Models, Molecular; D009154:Mutation; D052999:Quinazolinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D047028:Macrocyclic Compounds; D052999:Quinazolinones; D013450:Sulfones; D017361:Viral Nonstructural Proteins; C000603531:MK-2748; C000600429:MK-6325; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: MK-2748; MK-6325; antiviral agents; hepatitis C; macrocycles