Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.
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.
McCauley
John A
JA
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. john_mccauley@merck.com
McIntyre
Charles J
CJ
Rudd
Michael T
MT
Nguyen
Kevin T
KT
Romano
Joseph J
JJ
Butcher
John W
JW
Gilbert
Kevin F
KF
Bush
Kimberly J
KJ
Holloway
M Katharine
MK
Swestock
John
J
Wan
Bang-Lin
BL
Carroll
Steven S
SS
DiMuzio
Jillian M
JM
Graham
Donald J
DJ
Ludmerer
Steven W
SW
Mao
Shi-Shan
SS
Stahlhut
Mark W
MW
Fandozzi
Christine M
CM
Trainor
Nicole
N
Olsen
David B
DB
Vacca
Joseph P
JP
Liverton
Nigel J
NJ
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
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