Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

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...

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Published inACS medicinal chemistry letters Vol. 3; no. 4; pp. 332 - 336
Main Authors Harper, Steven, McCauley, John A, Rudd, Michael T, Ferrara, Marco, DiFilippo, Marcello, Crescenzi, Benedetta, Koch, Uwe, Petrocchi, Alessia, Holloway, M. Katharine, Butcher, John W, Romano, Joseph J, Bush, Kimberly J, Gilbert, Kevin F, McIntyre, Charles J, Nguyen, Kevin T, Nizi, Emanuela, Carroll, Steven S, Ludmerer, Steven W, Burlein, Christine, DiMuzio, Jillian M, Graham, Donald J, McHale, Carolyn M, Stahlhut, Mark W, Olsen, David B, Monteagudo, Edith, Cianetti, Simona, Giuliano, Claudio, Pucci, Vincenzo, Trainor, Nicole, Fandozzi, Christine M, Rowley, Michael, Coleman, Paul J, Vacca, Joseph P, Summa, Vincenzo, Liverton, Nigel J
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 12.04.2012
Subjects
Letter
MK-5172
genotype 3a
macrocycle
HCV
hepatitis C
mutant enzymes
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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.
AbstractList 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.
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.
Author Harper, Steven
Gilbert, Kevin F
Ferrara, Marco
McCauley, John A
Carroll, Steven S
Koch, Uwe
Stahlhut, Mark W
Crescenzi, Benedetta
Nizi, Emanuela
DiMuzio, Jillian M
Trainor, Nicole
Rowley, Michael
Butcher, John W
Nguyen, Kevin T
DiFilippo, Marcello
Burlein, Christine
Coleman, Paul J
Rudd, Michael T
Petrocchi, Alessia
Pucci, Vincenzo
Giuliano, Claudio
Holloway, M. Katharine
Summa, Vincenzo
Fandozzi, Christine M
Romano, Joseph J
Olsen, David B
Monteagudo, Edith
Vacca, Joseph P
Liverton, Nigel J
McHale, Carolyn M
Bush, Kimberly J
McIntyre, Charles J
Ludmerer, Steven W
Cianetti, Simona
Graham, Donald J
AuthorAffiliation Medicinal Chemistry
Merck Research Laboratories
IRBM, Merck Research Laboratories
Molecular Modeling
Chemistry, Modeling and Informatics
Antiviral Research
Drug Metabolism
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genotype 3a
macrocycle
HCV
hepatitis C
mutant enzymes
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Snippet 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...
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...
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Title Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor
URI http://dx.doi.org/10.1021/ml300017p
https://www.ncbi.nlm.nih.gov/pubmed/24900473
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Volume 3
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