Research Topics
| Nicholas D SmithSummaryAffiliation: Merck Research Laboratories Country: USA Publications
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Publications
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 antagonistSteve 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...- Water soluble prodrug of a COX-2 selective inhibitor suitable for intravenous administration in models of cerebral ischemiaNicholas 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... - 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].. - Discovery of highly potent, selective, orally bioavailable, metabotropic glutamate subtype 5 (mGlu5) receptor antagonists devoid of cytochrome P450 1A2 inhibitory activityNicholas 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... 
Identification of KD5170: a novel mercaptoketone-based histone deacetylase inhibitorJoseph 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...- 2-(2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl) pyridine: a highly potent, orally active, metabotropic glutamate subtype 5 (mGlu5) receptor antagonistDehua 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.... - 3-[Substituted]-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitriles: identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonistsLida 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... - 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 modelsCeline 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... - 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... - Alpha-mercaptoketone based histone deacetylase inhibitorsPaul 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... - Pharmacological characterization of KLYP961, a dual inhibitor of inducible and neuronal nitric-oxide synthasesKent 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... - Novel approach to pro-drugs of lactones: water soluble imidate and ortho-ester derivatives of a furanone-based COX-2 selective inhibitorSteve 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... - Heterocycle-substituted proline dipeptides as potent VLA-4 antagonistsThomas 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... - KLYP956 is a non-imidazole-based orally active inhibitor of nitric-oxide synthase dimerizationKent 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... - Expedited SAR study of an mGluR5 antagonists: generation of a focused library using a solution-phase Suzuki coupling methodologyBrian 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... - 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activityNicholas 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... - KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivoChristian 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... - 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... - Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activityJeffrey 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... 
Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormoneMark 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....- Total synthesis of ionomycin using ring-opening strategiesMark 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...