Nicholas D Smith

Summary

Affiliation: Merck Research Laboratories
Country: USA

Publications

  1. ncbi request reprint 3-[3-Fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine: a highly potent and orally bioavailable metabotropic glutamate subtype 5 (mGlu5) receptor antagonist
    Steve F Poon
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:5477-80. 2004
  2. ncbi request reprint Water soluble prodrug of a COX-2 selective inhibitor suitable for intravenous administration in models of cerebral ischemia
    Nicholas D Smith
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 15:3197-200. 2005
  3. ncbi request reprint One-step synthesis of 3-aryl- and 3,4-diaryl-(1H)-pyrroles using tosylmethyl isocyanide (TOSMIC)
    Nicholas D Smith
    Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA
    Org Lett 4:3537-9. 2002
  4. ncbi request reprint Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activity
    Nicholas D Smith
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:5481-4. 2004
  5. doi request reprint Identification of KD5170: a novel mercaptoketone-based histone deacetylase inhibitor
    Joseph E Payne
    Department of Chemistry, Kalypsys, Inc, 10420 Wateridge Circle, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 18:6093-6. 2008
  6. ncbi request reprint 2-(2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl) pyridine: a highly potent, orally active, metabotropic glutamate subtype 5 (mGlu5) receptor antagonist
    Dehua Huang
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:5473-6. 2004
  7. ncbi request reprint 3-[Substituted]-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitriles: identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonists
    Lida R Tehrani
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121 1140, USA
    Bioorg Med Chem Lett 15:5061-4. 2005
  8. doi request reprint Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models
    Celine Bonnefous
    Department of Chemistry, Kalypsys Inc, 10420 Wateridge Circle, San Diego, CA 92121, USA
    J Med Chem 52:3047-62. 2009
  9. doi request reprint Discovery of dual inducible/neuronal nitric oxide synthase (iNOS/nNOS) inhibitor development candidate 4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one (KD7332) part 2: identification of a novel, potent, and selective
    Joseph E Payne
    Department of Chemistry, Kalypsys, Inc, 10420 Wateridge Circle, San Diego, California 92121, USA
    J Med Chem 53:7739-55. 2010
  10. doi request reprint Alpha-mercaptoketone based histone deacetylase inhibitors
    Paul L Wash
    Department of Chemistry, Kalypsys, Inc, 10420 Wateridge Circle, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 18:6482-5. 2008

Collaborators

Detail Information

Publications21

  1. ncbi request reprint 3-[3-Fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine: a highly potent and orally bioavailable metabotropic glutamate subtype 5 (mGlu5) receptor antagonist
    Steve F Poon
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:5477-80. 2004
    ..Synthesis of a series of four-ring tetrazoles led to the discovery of 3-[3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine, a highly potent, brain penetrant, azole-based mGlu5 receptor antagonist...
  2. ncbi request reprint Water soluble prodrug of a COX-2 selective inhibitor suitable for intravenous administration in models of cerebral ischemia
    Nicholas D Smith
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 15:3197-200. 2005
    ..Constant infusion studies using 17 demonstrate that extrapolated brain levels of 16 may be maintained for over 24h in rats...
  3. ncbi request reprint One-step synthesis of 3-aryl- and 3,4-diaryl-(1H)-pyrroles using tosylmethyl isocyanide (TOSMIC)
    Nicholas D Smith
    Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA
    Org Lett 4:3537-9. 2002
    ..Optimal conditions were found to be NaOtBu in DMSO. The methodology was particularly efficient (yields > 65%) when electron poor aryl groups were attached to the alkene.[ reaction: see text]..
  4. ncbi request reprint Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activity
    Nicholas D Smith
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:5481-4. 2004
    ..This led to highly potent, selective and orally bioavailable 2-imidazolyl tetrazoles such as (10) that are devoid of cytochrome P450 inhibitory activity...
  5. doi request reprint Identification of KD5170: a novel mercaptoketone-based histone deacetylase inhibitor
    Joseph E Payne
    Department of Chemistry, Kalypsys, Inc, 10420 Wateridge Circle, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 18:6093-6. 2008
    ..KD5170 exhibits robust and sustained histone H3 hyperacetylation in HCT-116 xenograft tumors following single oral or i.v. dose and inhibition of tumor growth following chronic dosing...
  6. ncbi request reprint 2-(2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl) pyridine: a highly potent, orally active, metabotropic glutamate subtype 5 (mGlu5) receptor antagonist
    Dehua Huang
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:5473-6. 2004
    ....
  7. ncbi request reprint 3-[Substituted]-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitriles: identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonists
    Lida R Tehrani
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121 1140, USA
    Bioorg Med Chem Lett 15:5061-4. 2005
    ..In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy...
  8. doi request reprint Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models
    Celine Bonnefous
    Department of Chemistry, Kalypsys Inc, 10420 Wateridge Circle, San Diego, CA 92121, USA
    J Med Chem 52:3047-62. 2009
    ..Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model...
  9. doi request reprint Discovery of dual inducible/neuronal nitric oxide synthase (iNOS/nNOS) inhibitor development candidate 4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one (KD7332) part 2: identification of a novel, potent, and selective
    Joseph E Payne
    Department of Chemistry, Kalypsys, Inc, 10420 Wateridge Circle, San Diego, California 92121, USA
    J Med Chem 53:7739-55. 2010
    ..Further 42 did not affect motor coordination up to doses of 1000 mg/kg, demonstrating a wide therapeutic margin...
  10. doi request reprint Alpha-mercaptoketone based histone deacetylase inhibitors
    Paul L Wash
    Department of Chemistry, Kalypsys, Inc, 10420 Wateridge Circle, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 18:6482-5. 2008
    ..Lead optimization of the screening hit, led to a number of potent HDAC inhibitors. In particular, alpha-mercaptoketone 19y (KD5150) exhibited nanomolar in vitro activity and inhibition of tumor growth in vivo...
  11. doi request reprint Pharmacological characterization of KLYP961, a dual inhibitor of inducible and neuronal nitric-oxide synthases
    Kent T Symons
    Department of Biology, Kalypsys Inc, San Diego, California, USA
    J Pharmacol Exp Ther 336:468-78. 2011
    ..o.) and a greater potency than gabapentin. In summary, KLYP961 represents an ideal tool with which to probe the physiological role of NO derived from iNOS and nNOS in human pain and inflammatory states...
  12. ncbi request reprint Novel approach to pro-drugs of lactones: water soluble imidate and ortho-ester derivatives of a furanone-based COX-2 selective inhibitor
    Steve F Poon
    Department of Medicinal Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 15:2259-63. 2005
    ..Transforming the lactone moiety of the furanone to an imidate or an ortho-ester with a hydrophilic, endogenous appendage resulted in water soluble pro-drugs that converted to the parent drug in vivo...
  13. doi request reprint Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists
    Thomas S Reger
    Department of Medicinal Chemistry, Merck Research Laboratories, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 20:1173-6. 2010
    ..A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics...
  14. doi request reprint KLYP956 is a non-imidazole-based orally active inhibitor of nitric-oxide synthase dimerization
    Kent T Symons
    Department of Biology, Kalypsys Inc, San Diego, CA, USA
    Mol Pharmacol 76:153-62. 2009
    ..KLYP956 thus represents the first nonimidazole-based inhibitor of iNOS and nNOS dimerization and provides a novel pharmaceutical alternative to previously described substrate competitive inhibitors...
  15. ncbi request reprint Expedited SAR study of an mGluR5 antagonists: generation of a focused library using a solution-phase Suzuki coupling methodology
    Brian Eastman
    Department of Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA
    Bioorg Med Chem Lett 14:5485-8. 2004
    ..In addition, dimethylisoxazole, as a heterocyclic replacement for the phenylic ring of the lead compound, was also identified by this approach...
  16. ncbi request reprint 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity
    Nicholas D P Cosford
    Merck Research Laboratories, MRLSDB2, 3535, General Atomics Court, San Diego, California 92121, USA
    J Med Chem 46:204-6. 2003
    ..Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety...
  17. doi request reprint KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo
    Christian A Hassig
    Kalypsys, Inc, 10420 Wateridge Circle, San Diego, CA 92121, USA
    Mol Cancer Ther 7:1054-65. 2008
    ..The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent...
  18. doi request reprint Characterization of alpha(4)beta(1) (CD49d/CD29) on equine leukocytes: potential utility of a potent alpha(4)beta(1) (CD49d/CD29) receptor antagonist in the treatment of equine heaves (recurrent airway obstruction)
    Kelly M Treonze
    Department of Immunology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
    Vet Immunol Immunopathol 130:79-87. 2009
    ..3 mg/kg, receptor blockade of >80% was observed out to 24 h with a concomitant leukocytosis. We believe that Compound B possesses suitable intrinsic and pharmacological properties to be evaluated clinically in horses affected by RAO...
  19. ncbi request reprint Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity
    Jeffrey Roppe
    J Med Chem 47:4645-8. 2004
    ..Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED(50) = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing...
  20. pmc Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormone
    Mark J Holness
    Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, Barts and The London, Queen Mary s School of Medicine and Dentistry, University of London, London, UK
    Biochem J 369:687-95. 2003
    ....
  21. ncbi request reprint Total synthesis of ionomycin using ring-opening strategies
    Mark Lautens
    Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St George St, Toronto, Ontario M5S 3H6, Canada
    Org Lett 4:1879-82. 2002
    ..The synthesis demonstrates the utility of ring-opening methodologies as applied to the synthesis of polypropionate and deoxypolypropionate subunits, which are found in two of the four fragments in the synthesis...