title: Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
abstract: A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. john_mccauley@merck.com
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.forename: Charles J
authors.initials: CJ
authors.lastname: McIntyre
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nguyen
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Romano
authors.forename: John W
authors.initials: JW
authors.lastname: Butcher
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gilbert
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Bush
authors.forename: M Katharine
authors.initials: MK
authors.lastname: Holloway
authors.forename: John
authors.initials: J
authors.lastname: Swestock
authors.forename: Bang-Lin
authors.initials: BL
authors.lastname: Wan
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.forename: Jillian M
authors.initials: JM
authors.lastname: DiMuzio
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Graham
authors.forename: Steven W
authors.initials: SW
authors.lastname: Ludmerer
authors.forename: Shi-Shan
authors.initials: SS
authors.lastname: Mao
authors.forename: Mark W
authors.initials: MW
authors.lastname: Stahlhut
authors.forename: Christine M
authors.initials: CM
authors.lastname: Fandozzi
authors.forename: Nicole
authors.initials: N
authors.lastname: Trainor
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003521:Cyclopropanes; D004285:Dogs; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000201:enzymology*; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008099:Liver / Q000378:metabolism; D008253:Macaca mulatta; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D015394:Molecular Structure; D002679:Pan troglodytes; D011392:Proline / Q000031:analogs & derivatives; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014764:Viral 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; D003521:Cyclopropanes; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine; D047028:Macrocyclic Compounds; D011392:Proline; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; D014764:Viral 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; C540393:vaniprevir