Ming Tain Lai

Summary

Affiliation: Merck Research Laboratories
Country: USA

Publications

  1. pmc Distinct mutation pathways of non-subtype B HIV-1 during in vitro resistance selection with nonnucleoside reverse transcriptase inhibitors
    Ming Tain Lai
    Department of Antiviral Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
    Antimicrob Agents Chemother 54:4812-24. 2010
  2. ncbi request reprint 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
  3. pmc Antiviral activity of MK-4965, a novel nonnucleoside reverse transcriptase inhibitor
    Ming Tain Lai
    Department of Antiviral Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA
    Antimicrob Agents Chemother 53:2424-31. 2009
  4. ncbi request reprint Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities
    Ming Tain Lai
    Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
    J Biol Chem 278:22475-81. 2003
  5. doi request reprint The design and synthesis of diaryl ether second generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency versus key clinical mutations
    Thomas 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
  6. ncbi request reprint A presenilin-independent aspartyl protease prefers the gamma-42 site cleavage
    Ming Tain Lai
    Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA
    J Neurochem 96:118-25. 2006
  7. ncbi request reprint Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases
    Craig A Coburn
    Department of Medicinal Chemistry, Merck Research Laoratories, West Point, PA 19486 0004, USA
    J Med Chem 47:6117-9. 2004
  8. doi request reprint Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif
    Dai 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
  9. doi request reprint Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses
    Dai 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
  10. ncbi request reprint Design and synthesis of 2,3,5-substituted imidazolidin-4-one inhibitors of BACE-1
    James C Barrow
    Department of Medicinal Chemistry, Merck Research Laboratories, P O Box 4, WP14 1, West Point, PA 19486, USA
    ChemMedChem 2:995-9. 2007

Detail Information

Publications38

  1. pmc Distinct mutation pathways of non-subtype B HIV-1 during in vitro resistance selection with nonnucleoside reverse transcriptase inhibitors
    Ming 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...
  2. ncbi request reprint 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...
  3. pmc Antiviral activity of MK-4965, a novel nonnucleoside reverse transcriptase inhibitor
    Ming 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...
  4. ncbi request reprint Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities
    Ming 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...
  5. doi request reprint The design and synthesis of diaryl ether second generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency versus key clinical mutations
    Thomas 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
    ....
  6. ncbi request reprint A presenilin-independent aspartyl protease prefers the gamma-42 site cleavage
    Ming Tain Lai
    Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA
    J Neurochem 96:118-25. 2006
    ..More importantly, the PSIG activity displays a distinct preference in mediating the 42-site cleavage over the 40-site cleavage, thereby generating Abeta42 as the predominant product...
  7. ncbi request reprint Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases
    Craig 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...
  8. doi request reprint Biaryl ethers as potent allosteric inhibitors of reverse transcriptase and its key mutant viruses: aryl substituted pyrazole as a surrogate for the pyrazolopyridine motif
    Dai 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
    ....
  9. doi request reprint Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses
    Dai 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...
  10. ncbi request reprint Design and synthesis of 2,3,5-substituted imidazolidin-4-one inhibitors of BACE-1
    James C Barrow
    Department of Medicinal Chemistry, Merck Research Laboratories, P O Box 4, WP14 1, West Point, PA 19486, USA
    ChemMedChem 2:995-9. 2007
  11. doi request reprint Rapid P1 SAR of brain penetrant tertiary carbinamine derived BACE inhibitors
    Hong 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...
  12. ncbi request reprint Biochemical and cell-based assays for characterization of BACE-1 inhibitors
    Beth L Pietrak
    Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
    Anal Biochem 342:144-51. 2005
    ..To illustrate the use of these assays, the properties of a potent, cell-active BACE-1 inhibitor are described...
  13. doi request reprint SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition
    Hemaka 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...
  14. ncbi request reprint Conformationally biased P3 amide replacements of beta-secretase inhibitors
    Shawn 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...
  15. ncbi request reprint Rational design and synthesis of selective BACE-1 inhibitors
    Stephen F Brady
    Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
    Bioorg Med Chem Lett 14:601-4. 2004
    ..The selectivity of BACE 1 inhibitors versus cathepsin D and renin was enhanced 120-fold by replacing the hydrophobic propyl group with a hydrophilic propionic acid group...
  16. ncbi request reprint Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics
    Amy S Espeseth
    Biological Chemistry, Medicinal Chemistry, and Automated Biotechnology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
    J Biol Chem 280:17792-7. 2005
    ..These studies demonstrate that APP binding agents can affect its processing through multiple pathways, providing proof of concept for novel strategies aimed at selectively modulating Abeta production...
  17. ncbi request reprint Beta-secretase (BACE-1) inhibitors: accounting for 10s loop flexibility using rigid active sites
    Georgia 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...
  18. doi request reprint 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 viruses
    Thomas 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
    ....
  19. doi request reprint Assessment of the susceptibility of mutant HIV-1 to antiviral agents
    Ying Jie Wang
    Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA
    J Virol Methods 165:230-7. 2010
    ....
  20. ncbi request reprint Evaluating scoring functions for docking and designing beta-secretase inhibitors
    M 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...
  21. pmc Antiviral activity and in vitro mutation development pathways of MK-6186, a novel nonnucleoside reverse transcriptase inhibitor
    Meiqing 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)...
  22. ncbi request reprint 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...
  23. doi request reprint Design and synthesis of pyridone inhibitors of non-nucleoside reverse transcriptase
    Robert 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...
  24. ncbi request reprint Monitoring the development of non-nucleoside reverse transcriptase inhibitor-associated resistant HIV-1 using an electrochemiluminescence-based reverse transcriptase polymerase assay
    Vandna 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...
  25. ncbi request reprint gamma-Secretase: characterization and implication for Alzheimer disease therapy
    Min Xu
    Department of Biological Chemistry, Merck Research Laboratories, WP16 206, West Point, PA 19486, USA
    Neurobiol Aging 23:1023-30. 2002
    ..Presenilin/gamma-secretase as a potential target for AD therapy and its role in regulated intramembrane proteolysis are discussed...
  26. ncbi request reprint BACE-1 inhibition by a series of psi[CH2NH] reduced amide isosteres
    Craig 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...
  27. doi request reprint Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptase
    Robert 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...
  28. ncbi request reprint 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 cells
    Xiao Ping Shi
    Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
    J Alzheimers Dis 7:139-48; discussion 173-80. 2005
    ..A BACE inhibitor blocked the processing of the APP_NFEV beta-site in vitro and in cells. 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...
  29. ncbi request reprint Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors
    Stacey 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...
  30. doi request reprint Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase
    James 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...
  31. ncbi request reprint Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind beta-secretase in a N-terminal 10s-loop down conformation
    Shaun R Stauffer
    Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
    Bioorg Med Chem Lett 17:1788-92. 2007
    ....
  32. doi request reprint Purification of untagged HIV-1 reverse transcriptase by affinity chromatography
    Meiqing 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...
  33. doi request reprint Substituted tetrahydroquinolines as potent allosteric inhibitors of reverse transcriptase and its key mutants
    Dai 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...
  34. pmc In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor
    Ming Tain Lai
    Merck Research Laboratories, West Point, Pennsylvania, USA
    Antimicrob Agents Chemother 58:1652-63. 2014
    ..Taken together, these in vitro data suggest that MK-1439 possesses the desired properties for further development as a new antiviral agent. ..
  35. ncbi request reprint 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...
  36. doi request reprint 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 primates
    Sethu 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...
  37. doi request reprint Discovery of aminoheterocycles as a novel beta-secretase inhibitor class: pH dependence on binding activity part 1
    Shawn 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...
  38. ncbi request reprint Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain
    Shawn J Stachel
    Departments of Medicinal Chemistry, Biological Chemistry, Pain and Migraine, Molecular Systems, and Structural Biology, Merck Research Laboratories, P O Box 4, West Point, Pennsylvania 19486, United States
    J Med Chem 57:5800-16. 2014
    ..Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors. ..