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Dive into the research topics where Kevin Nguyen is active.

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Featured researches published by Kevin Nguyen.


Journal of Medicinal Chemistry | 2010

Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

John A. McCauley; Charles J. Mcintyre; Michael T. Rudd; Kevin Nguyen; Joseph J. Romano; John W. Butcher; Kevin F. Gilbert; Kimberly J. Bush; M. Katharine Holloway; John Swestock; Bang-Lin Wan; Steven S. Carroll; Jillian DiMuzio; Donald J. Graham; Steven W. Ludmerer; Shi-Shan Mao; Mark Stahlhut; Christine Fandozzi; Nicole Trainor; David B. Olsen; Joseph P. Vacca; Nigel J. Liverton

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.


ACS Medicinal Chemistry Letters | 2012

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

Steven Harper; John A. McCauley; Michael T. Rudd; Marco Ferrara; Marcello DiFilippo; Benedetta Crescenzi; Uwe Koch; Alessia Petrocchi; M. Katharine Holloway; John W. Butcher; Joseph J. Romano; Kimberly J. Bush; Kevin F. Gilbert; Charles J. Mcintyre; Kevin Nguyen; Emanuela Nizi; Steven S. Carroll; Steven W. Ludmerer; Christine Burlein; Jillian DiMuzio; Donald J. Graham; Carolyn McHale; Mark Stahlhut; David B. Olsen; Edith Monteagudo; Simona Cianetti; Claudio Giuliano; Vincenzo Pucci; Nicole Trainor; Christine Fandozzi

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.


PLOS ONE | 2013

An Ultra High-Throughput, Whole-Animal Screen for Small Molecule Modulators of a Specific Genetic Pathway in Caenorhabditis elegans

Chi K. Leung; Ying Wang; Siobhan Malany; Andrew Deonarine; Kevin Nguyen; Stefan Vasile; Keith P. Choe

High-throughput screening (HTS) is a powerful approach to drug discovery, but many lead compounds are found to be unsuitable for use in vivo after initial screening. Screening in small animals like C. elegans can help avoid these problems, but this system has been limited to screens with low-throughput or no specific molecular target. We report the first in vivo 1536-well plate assay for a specific genetic pathway in C. elegans. Our assay measures induction of a gene regulated by SKN-1, a master regulator of detoxification genes. SKN-1 inhibitors will be used to study and potentially reverse multidrug resistance in parasitic nematodes. Screens of two small commercial libraries and the full Molecular Libraries Small Molecule Repository (MLSMR) of ∼364,000 compounds validate our platform for ultra HTS. Our platform overcomes current limitations of many whole-animal screens and can be widely adopted for other inducible genetic pathways in nematodes and humans.


Bioorganic & Medicinal Chemistry Letters | 2012

Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor

Patrick R. Maloney; Pasha Khan; Michael Hedrick; Palak Gosalia; Monika Milewski; Linda Li; Gregory P. Roth; Eduard Sergienko; Eigo Suyama; Eliot Sugarman; Kevin Nguyen; Alka Mehta; Stefan Vasile; Ying Su; Derek Stonich; Hung Nguyen; Fu-Yue Zeng; Arianna Mangravita Novo; Michael Vicchiarelli; Jena Diwan; Thomas Dy Chung; Layton H. Smith; Anthony B. Pinkerton

The recently discovered apelin/APJ system has emerged as a critical mediator of cardiovascular homeostasis and is associated with the pathogenesis of cardiovascular disease. A role for apelin/APJ in energy metabolism and gastrointestinal function has also recently emerged. We disclose the discovery and characterization of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221), a potent APJ functional antagonist in cell-based assays that is >37-fold selective over the closely related angiotensin II type 1 (AT1) receptor. ML221 was derived from an HTS of the ~330,600 compound MLSMR collection. This antagonist showed no significant binding activity against 29 other GPCRs, except to the κ-opioid and benzodiazepinone receptors (<50/<70%I at 10 μM). The synthetic methodology, development of structure-activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented.


Nature Chemical Biology | 2017

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11

Jing Li; Tanya Yakushi; Francesco Parlati; Andrew L. Mackinnon; Christian Perez; Yuyong Ma; Kyle P. Carter; Sharon Colayco; Gavin Magnuson; Brock Brown; Kevin Nguyen; Stefan Vasile; Eigo Suyama; Layton H. Smith; Eduard Sergienko; Anthony B. Pinkerton; Thomas Dy Chung; Amy E. Palmer; Ian Pass; Sonja Hess; Seth M. Cohen; Raymond J. Deshaies

The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.


Journal of Medicinal Chemistry | 2012

Discovery of a Plasmodium falciparum Glucose-6-phosphate Dehydrogenase 6-phosphogluconolactonase Inhibitor (R,Z)-N-((1-Ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (ML276) That Reduces Parasite Growth in Vitro

Janina Preuss; Patrick Maloney; Satyamaheshwar Peddibhotla; Michael Hedrick; Paul M. Hershberger; Palak Gosalia; Monika Milewski; Yujie Linda Li; Eliot Sugarman; Becky Hood; Eigo Suyama; Kevin Nguyen; Stefan Vasile; Eduard Sergienko; Arianna Mangravita-Novo; Michael Vicchiarelli; Danielle McAnally; Layton H. Smith; Gregory P. Roth; Jena Diwan; Thomas Dy Chung; Esther Jortzik; Stefan Rahlfs; Katja Becker; Anthony B. Pinkerton; Lars Bode

A high-throughput screen of the NIHs MLSMR collection of ∼340000 compounds was undertaken to identify compounds that inhibit Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD). PfG6PD is important for proliferating and propagating P. falciparum and differs structurally and mechanistically from the human orthologue. The reaction catalyzed by glucose-6-phosphate dehydrogenase (G6PD) is the first, rate-limiting step in the pentose phosphate pathway (PPP), a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. In P. falciparum , the bifunctional enzyme glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) catalyzes the first two steps of the PPP. Because P. falciparum and infected host red blood cells rely on accelerated glucose flux, they depend on the G6PD activity of PfGluPho. The lead compound identified from this effort, (R,Z)-N-((1-ethylpyrrolidin-2-yl)methyl)-2-(2-fluorobenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide, 11 (ML276), is a submicromolar inhibitor of PfG6PD (IC(50) = 889 nM). It is completely selective for the enzymes human isoform, displays micromolar potency (IC(50) = 2.6 μM) against P. falciparum in culture, and has good drug-like properties, including high solubility and moderate microsomal stability. Studies testing the potential advantage of inhibiting PfG6PD in vivo are in progress.


ACS Medicinal Chemistry Letters | 2011

Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure

Michael T. Rudd; John A. McCauley; John W. Butcher; Joseph J. Romano; Charles J. Mcintyre; Kevin Nguyen; Kevin F. Gilbert; Kimberly J. Bush; M. Katharine Holloway; John Swestock; Bang-Lin Wan; Steven S. Carroll; Jillian DiMuzio; Donald J. Graham; Steven W. Ludmerer; Mark Stahlhut; Christine Fandozzi; Nicole Trainor; David B. Olsen; Joseph P. Vacca; Nigel J. Liverton

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.


Journal of Medicinal Chemistry | 1999

Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of P38 mitogen-activated protein kinase

Nigel J. Liverton; John W. Butcher; Christopher F. Claiborne; David A. Claremon; Brian Libby; Kevin Nguyen; Steven M. Pitzenberger; Harold G. Selnick; Garry R. Smith; Andrew J. Tebben; Joseph P. Vacca; Sandor L. Varga; Lily Agarwal; Kim Dancheck; Amy J. Forsyth; Daniel S. Fletcher; Betsy Frantz; William A. Hanlon; Coral Harper; Scott J. Hofsess; Matthew Kostura; Jiunn Lin; Sylvie Luell; Edward A. O'Neill; Chad Orevillo; Margaret Pang; Janey Parsons; Anna Rolando; Yousif Sahly; Denise M. Visco


Journal of Medicinal Chemistry | 2007

Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist.

Nigel J. Liverton; Rodney A. Bednar; Bohumil Bednar; John W. Butcher; Christopher F. Claiborne; David A. Claremon; Michael E. Cunningham; Anthony G. DiLella; Stanley L. Gaul; Brian Libby; Elizabeth A. Lyle; Joseph J. Lynch; John A. McCauley; Scott D. Mosser; Kevin Nguyen; Gary L. Stump; Hong Sun; Hao Wang; James A. Yergey; Kenneth S. Koblan


Archive | 2013

Functional antagonists of the Apelin (APJ) receptor

Patrick Maloney; Pasha Khan; Michael Hedrick; Palak Gosalia; Monika Milewski; Linda Li; Gregory P. Roth; Eduard Sergienko; Eigo Suyama; Eliot Sugarman; Kevin Nguyen; Alka Mehta; Stefan Vasile; Ying Su; Derek Stonich; Hung Nguyen; Fu-Yue Zeng; Arianna Mangravita Novo; Michael Vicchiarelli; Jena Diwan; Thomas Dy Chung; Anthony B. Pinkerton; Layton H. Smith

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Paul Hershberger

United States Geological Survey

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Lars Bode

University of California

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