Research Topics
Genomes and GenesSpecies | Ming Tain LaiSummaryAffiliation: Merck Research Laboratories Country: USA Publications
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Publications
Distinct mutation pathways of non-subtype B HIV-1 during in vitro resistance selection with nonnucleoside reverse transcriptase inhibitorsMing Tain Lai
Department of Antiviral Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
Antimicrob Agents Chemother 54:4812-24. 2010..Thus, the interactions between NNRTIs and the residues in the NNRTIBPs of different subtypes may not be identical, leading to distinct mutation pathways during resistance selection in cell culture...
Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1)Shawn J Stachel
Department of Medicinal Chemistry, Merck Research Laboratories, P O Box 4, West Point, Pennsylvania 19486, USA
J Med Chem 47:6447-50. 2004..In addition to potent inhibition in a cell-based assay (IC50 < 100 nM), these inhibitors display impressive selectivity against other biologically relevant aspartyl proteases...- Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activitiesMing Tain Lai
Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
J Biol Chem 278:22475-81. 2003..The distinct yet overlapping enzymatic properties of the PS1 gamma-secretase complex and the PS2 gamma-secretase complex imply that these two putative aspartyl class proteases may contribute to different biological processes... - Antiviral activity of MK-4965, a novel nonnucleoside reverse transcriptase inhibitorMing Tain Lai
Department of Antiviral Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
Antimicrob Agents Chemother 53:2424-31. 2009..Taken together, these in vitro data show that MK-4965 possesses the desired properties for further development as a new NNRTI for the treatment of HIV-1 infection... 
The design and synthesis of diaryl ether second generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency versus key clinical mutationsThomas J Tucker
Department of Medicinal Chemistry, Merck Research Laboratories, WP14 3, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486 0004, USA
Bioorg Med Chem Lett 18:2959-66. 2008....- Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motifDai Shi Su
Department of Medicinal Chemistry and Structural Biology, Merck Research Laboratory, West Point, PA 19486, USA
Bioorg Med Chem Lett 20:4328-32. 2010.... - Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteasesCraig A Coburn
Department of Medicinal Chemistry, Merck Research Laoratories, West Point, PA 19486 0004, USA
J Med Chem 47:6117-9. 2004..Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors... - Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant virusesDai Shi Su
Department of Medicinal Chemistry and Structural Biology, Merck Research Laboratory, P O Box 4, West Point, Pennsylvania 19486, USA
J Med Chem 52:7163-9. 2009..The compound also exhibited a clean safety profile in preclinical safety studies... - Rapid P1 SAR of brain penetrant tertiary carbinamine derived BACE inhibitorsHong Zhu
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Bioorg Med Chem Lett 20:1779-82. 2010..This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF Abeta40 was observed... - SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibitionHemaka A Rajapakse
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Bioorg Med Chem Lett 20:1885-9. 2010..The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5... - Discovery of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): a potent, orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitor with improved potency against key mutant virusesThomas J Tucker
Departments of Medicinal Chemistry and Structural Biology, Merck Research Laboratories, WP14 3, 770 Sumneytown Pike, P O Box 4, West Point, Pennsylvania 19486 0004, USA
J Med Chem 51:6503-11. 2008.... - Beta-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sitesGeorgia B McGaughey
Department of Molecular Systems, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
Bioorg Med Chem Lett 17:1117-21. 2007..These X-ray structures were used to correlate K(i) values, which span over five orders of magnitude, with the calculated interaction energy, using the Merck Molecular Force Field for a series of 19 tertiary carbinamine inhibitors... - Conformationally biased P3 amide replacements of beta-secretase inhibitorsShawn J Stachel
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Bioorg Med Chem Lett 16:641-4. 2006..The studies resulted in the identification of the beta-secretase inhibitor 7m which has an in vitro IC(50)=35 nM. The synthesis and biological activities of these compounds are described... - Assessment of the susceptibility of mutant HIV-1 to antiviral agentsYing Jie Wang
Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA
J Virol Methods 165:230-7. 2010.... - Evaluating scoring functions for docking and designing beta-secretase inhibitorsM Katharine Holloway
Department of Molecular Systems, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA kate_
Bioorg Med Chem Lett 17:823-7. 2007..Both the PLP1 score and MMFFs interaction energy (E(inter)) performed as well or better than more computationally intensive methods for a set of substrate-based inhibitors, while the latter performed well for both sets of inhibitors... - Antiviral activity and in vitro mutation development pathways of MK-6186, a novel nonnucleoside reverse transcriptase inhibitorMeiqing Lu
Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania, USA
Antimicrob Agents Chemother 56:3324-35. 2012..More importantly, mutant viruses selected by MK-6186 showed FCs of <10 against EFV or etravirine (ETR), and the mutant viruses containing mutations selected by EFV or ETR were sensitive to MK-6186 (FCs of <10)... - Monitoring the development of non-nucleoside reverse transcriptase inhibitor-associated resistant HIV-1 using an electrochemiluminescence-based reverse transcriptase polymerase assayVandna Munshi
Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA
Anal Biochem 374:121-32. 2008..The magnitude of resistance of the resulting mutant viruses was assessed directly by the assay, eliminating the need for cloning, expressing, and purifying the RT mutants... - Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1)Hemaka A Rajapakse
Department of Medicinal Chemistry, Merck Research Laboratories, P O Box 4, West Point, Pennsylvania 19486, USA
J Med Chem 49:7270-3. 2006..Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1... - BACE-1 inhibition by a series of psi[CH2NH] reduced amide isosteresCraig A Coburn
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
Bioorg Med Chem Lett 16:3635-8. 2006..Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay... - Design and synthesis of pyridone inhibitors of non-nucleoside reverse transcriptaseRobert Gomez
Department of West Point Discovery Chemistry, Merck Research Labs, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486 0004, USA
Bioorg Med Chem Lett 21:7344-50. 2011..The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTI's... - Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptaseRobert Gomez
Departments of West Point Discovery Chemistry, Pennsylvania 19486 0004, United States
J Med Chem 54:7920-33. 2011..Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains... - Novel mutations introduced at the beta-site of amyloid beta protein precursor enhance the production of amyloid beta peptide by BACE1 in vitro and in cellsXiao Ping Shi
Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
J Alzheimers Dis 7:139-48; discussion 173-80. 2005..Our data indicates that the "NFEV" mutant is not only an enhanced substrate for BACE1 in vitro, but also a specific substrate for BACE1 in cells... - Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitorsStacey R Lindsley
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
Bioorg Med Chem Lett 17:4057-61. 2007..These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability... - Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretaseJames C Barrow
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
J Med Chem 51:6259-62. 2008..Using the crystal structure as a guide, potent compounds with good brain penetration were designed... - Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformationShaun R Stauffer
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Bioorg Med Chem Lett 17:1788-92. 2007.... - Purification of untagged HIV-1 reverse transcriptase by affinity chromatographyMeiqing Lu
Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA
Protein Expr Purif 71:231-9. 2010..Untagged RT was released from the column by reductive cleavage of the intein by DTT. These two methods significantly shorten the time required to purify untagged WT and mutant RTs... - Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutantsDai Shi Su
Department of Medicinal Chemistry and Structural Biology, Merck Research Laboratory, West Point, PA 19486, USA
Bioorg Med Chem Lett 19:5119-23. 2009..The SAR optimization, mutation profiles, preparation of compounds, and pharmacokinetic profile of compounds are described... - Novel indole-3-sulfonamides as potent HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs)Zhijian Zhao
Department of Medicinal Chemistry, Merck and Co, Inc, PO Box 4, West Point, PA 19486, USA
Bioorg Med Chem Lett 18:554-9. 2008..This Letter describes the design, synthesis, and biological evaluation of novel 3-indole sulfonamides as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) with balanced profiles against common HIV RT mutants K103N and Y181C... - Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1Shawn J Stachel
Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co, West Point, PA 19486, USA
Bioorg Med Chem Lett 19:2977-80. 2009..In addition to the elucidation of their binding profile, we have discovered a pH dependent effect on the binding affinity as a result of the intrinsic pK(a) of these inhibitors and the pH of the BACE-1 enzyme binding assay... - First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primatesSethu Sankaranarayanan
Department of Alzheimer s Research, WP 26A 2000, Merck Research Labs, 770 Sumneytown Pike, West Point, PA 19486, USA
J Pharmacol Exp Ther 328:131-40. 2009..These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate...