Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
ChemMedChem ; 10(4): 727-35, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25759009

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.


Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/enzymology , Macrocyclic Compounds/pharmacology , Quinazolinones/pharmacology , Sulfones/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Crystallography, X-Ray , Drug Discovery , Hepacivirus/drug effects , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacokinetics , Models, Molecular , Mutation , Quinazolinones/chemistry , Quinazolinones/pharmacokinetics , Rats , Sulfones/pharmacokinetics , Viral Nonstructural Proteins/genetics
2.
ACS Med Chem Lett ; 3(4): 332-6, 2012 Apr 12.
Article in English | MEDLINE | ID: mdl-24900473

ABSTRACT

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.

3.
ACS Med Chem Lett ; 2(3): 207-12, 2011 Mar 10.
Article in English | MEDLINE | ID: mdl-24900304

ABSTRACT

The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

4.
J Med Chem ; 53(6): 2443-63, 2010 Mar 25.
Article in English | MEDLINE | ID: mdl-20163176

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.


Subject(s)
Hepacivirus/enzymology , Indoles/pharmacology , Serine Proteinase Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Area Under Curve , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/metabolism , Cyclopropanes , Dogs , Drug Discovery , Drug Evaluation, Preclinical , Indoles/chemistry , Indoles/pharmacokinetics , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Isoindoles , Lactams, Macrocyclic , Leucine/analogs & derivatives , Liver/metabolism , Macaca mulatta , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacokinetics , Macrocyclic Compounds/pharmacology , Metabolic Clearance Rate , Models, Chemical , Molecular Structure , Pan troglodytes , Proline/analogs & derivatives , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Sulfonamides , Viral Nonstructural Proteins/metabolism , Viral Proteins/antagonists & inhibitors , Viral Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...