Publications by authors named "Benjamin R Bellenie"

6 Publications

  • Page 1 of 1

Achieving Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

J Med Chem 2020 04 10;63(8):4047-4068. Epub 2020 Apr 10.

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3,5)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2-benzo[]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184563PMC
April 2020

Aryl sulphonyl amides as potent agonists of the growth hormone secretagogue (ghrelin) receptor.

Bioorg Med Chem Lett 2009 Feb 14;19(3):684-7. Epub 2008 Dec 14.

Department of Medicinal Chemistry & DMPK, Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

As part of an on-going lead optimisation effort, a cross screening exercise identified an aryl sulphonyl amide hit that was optimised to afford a highly potent series of ghrelin receptor agonists.
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http://dx.doi.org/10.1016/j.bmcl.2008.12.042DOI Listing
February 2009

Discovery and optimization of highly ligand-efficient oxytocin receptor antagonists using structure-based drug design.

Bioorg Med Chem Lett 2009 Feb 24;19(3):990-4. Epub 2008 Nov 24.

GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North), Coldharbour Road, Harlow, Essex CM19 5AD, England, United Kingdom.

A novel oxytocin antagonist was identified by 'scaffold-hopping' using Cresset FieldScreen molecular field similarity searching. A single cycle of optimization driven by an understanding of the key pharmacophoric elements required for activity led to the discovery of a potent, selective and highly ligand-efficient oxytocin receptor antagonist. Selectivity over vasopressin receptors was rationalized based on differences in the structure of the natural ligands.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.064DOI Listing
February 2009

Discovery and optimisation of a potent and selective tertiary sulfonamide oxytocin antagonist.

Bioorg Med Chem Lett 2009 Jan 12;19(2):528-32. Epub 2008 Nov 12.

GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North), Coldharbour Road, Harlow, Essex CM19 5AD, England, UK.

The optimisation of a tertiary sulfonamide high-throughput screening hit is described. A combination of high-throughput chemistry, pharmacophore analysis and in silico PK profiling resulted in the discovery of potent sulfonamide oxytocin receptor antagonists with oral exposure and good selectivity over vasopressin receptors.
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http://dx.doi.org/10.1016/j.bmcl.2008.11.018DOI Listing
January 2009

Theoretical study on the selectivity of asymmetric sulfur ylide epoxidation reaction.

Org Lett 2004 Jul;6(15):2559-62

Unilever Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.

[structure: see text] We report the first theoretical studies on the asymmetric sulfonium ylide epoxidation reaction using a chiral sulfide that successfully reproduces the experimentally determined high enantiomeric excess. Calculations at the DFT level suggest that the transition states for the addition of the sulfonium ylide to benzaldehyde have energies which account for the observed enantioselectivity.
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http://dx.doi.org/10.1021/ol0491641DOI Listing
July 2004

Sulfonium ylide epoxidation reactions: methylene transfer.

Chem Commun (Camb) 2004 May 1(9):1076-7. Epub 2004 Apr 1.

Unilever Centre for Molecular Science Informatics, Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW.

Using a D-mannitol derived chiral sulfide, terminal epoxides are formed in up to 76% ee; the first example of double asymmetric induction in a sulfonium methylide epoxidation is reported and an improved method of generating sulfonium ylides is detailed.
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http://dx.doi.org/10.1039/b316653hDOI Listing
May 2004