Research Topics
| John W CladerSummaryAffiliation: Schering-Plough Research Institute Country: USA Publications
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Publications
Muscarinic receptor agonists and antagonists in the treatment of Alzheimer's diseaseJohn W Clader
Schering Plough Research Institute 2015 Galloping Hill Road Kenilworth, NJ 07033, USA
Curr Pharm Des 11:3353-61. 2005..In this review summarizes recent progress in the identification and characterization of selective muscarinic receptor ligands for the treatment of Alzheimer's disease...- Ezetimibe and other azetidinone cholesterol absorption inhibitorsJohn W Clader
Department of Cardiovascular and CNS Medicinal Chemistry, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033 1300, USA
Curr Top Med Chem 5:243-56. 2005..A.R. trends in this area... - Muscarinic M2 antagonists: anthranilamide derivatives with exceptional selectivity and in vivo activityJohn W Clader
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem 12:319-26. 2004..Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity... - The discovery of ezetimibe: a view from outside the receptorJohn W Clader
Cardiovascular and CNS Medicinal Chemistry Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-0539, USA
J Med Chem 47:1-9. 2004 - Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureasMark D McBriar
Department of Chemical Research and Department of Cardiovascular and Metabolic Diseases, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 0539, USA
J Med Chem 49:2294-310. 2006..In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study... - Oximino-piperidino-piperidine-based CCR5 antagonists. Part 2: synthesis, SAR and biological evaluation of symmetrical heteroaryl carboxamidesAnandan Palani
Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 13:709-12. 2003..A series of potent and orally bioavailable CCR5 antagonists containing symmetrical 2,6-dimethyl isonicotinamides and 2, 6-dimethyl pyrimidines amides were generated with enhanced affinity for the CCR5 receptor... - Synthesis of novel bicyclo[4.1.0]heptane and bicyclo[3.1.0]hexane derivatives as melanin-concentrating hormone receptor R1 antagonistsJing Su
Department of Chemical Research, Schering Plough Research Institute K15 2545, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 17:4845-50. 2007..Biological evaluation confirmed that these new analogs retained MCH R1 activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay... - Small conformationally restricted piperidine N-arylsulfonamides as orally active gamma-secretase inhibitorsHubert Josien
Department of Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07302, USA
Bioorg Med Chem Lett 17:5330-5. 2007..Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease... - Bicyclic[4.1.0]heptanes as phenyl replacements for melanin concentrating hormone receptor antagonistsRuo Xu
Department of Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033 0539, USA
Bioorg Med Chem 14:3285-99. 2006..Structure-activity relationships in this series were found to be very similar to those of the original biphenylamine series, suggesting that the two series have similar binding modes... - Discovery of amide and heteroaryl isosteres as carbamate replacements in a series of orally active gamma-secretase inhibitorsMark D McBriar
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 18:215-9. 2008..In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of Abeta levels upon oral dosing in a transgenic murine model of Alzheimer's disease... - 2,6-Disubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitorsDmitri A Pissarnitski
Department of Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 17:57-62. 2007..The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned... - Novel orally active morpholine N-arylsulfonamides gamma-secretase inhibitors with low CYP 3A4 liabilityHubert Josien
Department of CV and CNS Medicinal Chemistry, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 19:6032-7. 2009..This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Abeta levels in Tg CRND8 mice upon oral administration were identified... - Discovery of 2,4,6-trisubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitorsHongmei Li
Department of Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 17:6290-4. 2007..Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported... - Discovery of gamma-secretase inhibitors efficacious in a transgenic animal model of Alzheimer's diseaseTheodros Asberom
Department of Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 17:511-6. 2007..Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk... - Bicyclo[3.1.0]hexyl urea melanin concentrating hormone (MCH) receptor-1 antagonists: impacting hERG liability via aryl modificationsMark D McBriar
Schering Plough Research Institute, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 16:4262-5. 2006..This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series... - Biological evaluation and interconversion studies of rotamers of SCH 351125, an orally bioavailable CCR5 antagonistAnandan Palani
Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 13:705-8. 2003..The separation and biological evaluation of rotamers as well as interconversion studies on rotamers of our clinical candidate SCH 351125 are described... - Synthesis of fluorescent biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitorsDuane A Burnett
Schering Plough Research Institute, 2015 Galloping Hill Road MS 2800, Kenilworth, NJ 07033 0539, USA
Bioorg Med Chem Lett 12:315-8. 2002..Biological testing reveals that they are potent CAIs and are suitable tools for the investigation of the azetidinone CAI mechanism of action (MOA)... - Synthesis and SAR study of tricyclic sulfones as γ-secretase inhibitors: C-6 and C-8 positionsJing Su
Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 21:3447-51. 2011..Several functional groups were found to be well tolerated at C-6 and C-8 positions. Selective combination of C-6 and C-8 modification resulted in new tricyclic sulfone analogs with efficacy in in vivo mouse Aβ(40) lowering model... - Biaryl ureas as potent and orally efficacious melanin concentrating hormone receptor 1 antagonists for the treatment of obesityAnandan Palani
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
J Med Chem 48:4746-9. 2005..Compound 1 exhibited oral efficacy in chronic (28 d) rodent models at 3-30 mpk showing significant reduction in food intake and weight gain relative to controls... - Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male EDCraig D Boyle
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 15:2365-9. 2005..In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile... - Design, synthesis, and structure-activity relationship studies of N-arylsulfonyl morpholines as γ-secretase inhibitorsHongmei Li
Department of Chemical Research, Merck Research Lab, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 20:6606-9. 2010..Several different small alkyl groups are installed on the left-hand side to lower the CYP3A4 liability while maintaining excellent in vitro potency... - SAR study of bicyclo[4.1.0]heptanes as melanin-concentrating hormone receptor R1 antagonists: taming hERGJing Su
Department of Chemical Research, Schering Plough Research Institute K15 2545, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem 15:5369-85. 2007..Further replacement of the distal phenyl group with heteroaryl groups in the cyclohexene series provided compounds such as 28l with excellent ex vivo activity with much reduced hERG liability... - Solution-phase parallel synthesis of carbamates as gamma-secretase inhibitorsHenry A Vaccaro
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
J Comb Chem 10:56-62. 2008..The prepared compounds were assessed in the gamma-secretase inhibition assay and demonstrated activity with IC 50 values in the range from 1 microM to 5 nM, with the activity of 7 compounds being better than 10 nM... - Biaryl diamides as potent melanin concentrating hormone receptor 1 antagonistsAnandan Palani
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 15:5234-6. 2005..This paper describes one of the strategies incorporated to remove the highly mutagenic biarylaniline present in an otherwise promising biaryl urea series... - Isopropyl amide derivatives of potent and selective muscarinic M2 receptor antagonistsAnandan Palani
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 14:1791-4. 2004..Isopropyl amides 19 and 31 are highly potent, selective and low molecular weight M(2) receptor antagonists with structural features different from our clinical candidate 1... - Tetrahydroquinoline sulfonamides as gamma-secretase inhibitorsTheodros Asberom
Department of Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 17:205-7. 2007..The development of a novel series of tetrahydroquinoline-derived gamma-secretase inhibitors for the potential treatment of Alzheimer's disease is described... - Synthesis of iodinated biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitorsDuane A Burnett
Schering Plough Research Institute, 2015 Galloping Hill Road MS 2800, Kenilworth, NJ 07033 0539, USA
Bioorg Med Chem Lett 12:311-4. 2002..They are structurally consistent with the allowable SAR of the 2-azetidinone class of cholesterol absorption inhibitors... - Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouseLynn A Hyde
Department of Neurobiology, Schering Plough Research Institute, Kenilworth, New Jersey 07033, USA
J Pharmacol Exp Ther 319:1133-43. 2006.... - Discovery of bicycloalkyl urea melanin concentrating hormone receptor antagonists: orally efficacious antiobesity therapeuticsMark D McBriar
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033 0539, USA
J Med Chem 48:2274-7. 2005..Herein, we report the discovery of a novel, orally active series of MCH-R1 antagonists that exhibit in vivo efficacy in rodent obesity models... - Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activityAnandan Palani
Chemical Research, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
J Med Chem 45:3143-60. 2002.... - SAR development of polycyclic guanine derivatives targeted to the discovery of a selective PDE5 inhibitor for treatment of erectile dysfunctionDmitri A Pissarnitski
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Bioorg Med Chem Lett 14:1291-4. 2004..Development of structure-activity relationship of cyclic guanines I lead us to discovery of a potent and selective series of phosphodiesterase 5 inhibitors 52-59 (IC50=1.3-11.0 nM, PDE6/5=116-600)... 
Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entryFotini Tsamis
Microbiology and Immunology Department, Albert Einstein College of Medicine, Bronx, New York 10461, USA
J Virol 77:5201-8. 2003..We propose that the binding of small molecules to the transmembrane domain of CCR5 may disrupt the conformation of its extracellular domain, thereby inhibiting ligand binding to CCR5...- Interaction of small molecule inhibitors of HIV-1 entry with CCR5Christoph Seibert
Laboratory of Molecular Biology and Biochemistry, The Rockefeller University, New York, NY 10021, USA
Virology 349:41-54. 2006..These results provide a structural basis for understanding how specific antagonists interact with CCR5, and may be useful for the rational design of new, improved CCR5 ligands... - Design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitorsTao Guo
Pharmacopeia Drug Discovery, Inc, P O Box 5350, Princeton, NJ 08543 5350, USA
Bioorg Med Chem Lett 17:3010-3. 2007..In this paper, the design, synthesis, and evaluation of tetrahydroquinoline and pyrrolidine sulfonamide carbamates as gamma-secretase inhibitors are described... - HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 useAlexandra Trkola
Division of Infectious Diseases, Department of Medicine, University Hospital Zurich, 8091 Zurich, Switzerland
Proc Natl Acad Sci U S A 99:395-400. 2002..Instead, HIV-1 acquires the ability to use CCR5 despite the inhibitor, first by requiring lower levels of CCR5 for entry and then probably by using the drug-bound form of the receptor...