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Start Over Author "Luckhurst CA" Publisher elsevier science ltd
5 results on '"Luckhurst CA"'

1. Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor.

Author

Luckhurst CA, Aziz O, Beaumont V, Bürli RW, Breccia P, Maillard MC, Haughan AF, Lamers M, Leonard P, Matthews KL, Raphy G, Stott AJ, Munoz-Sanjuan I, Thomas B, Wall M, Wishart G, Yates D, and Dominguez C

Subjects
Animals, Dose-Response Relationship, Drug, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors chemistry, Humans, Hydroxamic Acids chemical synthesis, Hydroxamic Acids chemistry, Mice, Molecular Structure, Structure-Activity Relationship, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Hydroxamic Acids pharmacology
Abstract

We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC 50 levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2019
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2. Scaffold-hopping with zwitterionic CCR3 antagonists: identification and optimisation of a series with good potency and pharmacokinetics leading to the discovery of AZ12436092.

Author

Bahl A, Barton P, Bowers K, Caffrey MV, Denton R, Gilmour P, Hawley S, Linannen T, Luckhurst CA, Mochel T, Perry MW, Riley RJ, Roe E, Springthorpe B, Stein L, and Webborn P

Subjects
Animals, Humans, Inhibitory Concentration 50, Molecular Structure, Rats, Drug Discovery, Piperidines chemistry, Piperidines pharmacokinetics, Receptors, CCR3 antagonists & inhibitors
Abstract

The discovery and optimisation of a series of zwitterionic CCR3 antagonists is described. Optimisation of the structure led to AZ12436092, a compound with excellent selectivity over activity at hERG and outstanding pharmacokinetics in preclinical species., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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3. The discovery of CCR3/H1 dual antagonists with reduced hERG risk.

Author

Bahl A, Barton P, Bowers K, Brough S, Evans R, Luckhurst CA, Mochel T, Perry MW, Rigby A, Riley RJ, Sanganee H, Sisson A, and Springthorpe B

Subjects
Animals, Drug Interactions, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Histamine H1 Antagonists pharmacokinetics, Molecular Structure, Piperidines chemistry, Rats, Risk Factors, Drug Discovery, Histamine H1 Antagonists chemistry, Receptors, CCR3 antagonists & inhibitors
Abstract

A series of dual CCR3/H(1) antagonists based on a bispiperidine scaffold were discovered. Introduction of an acidic group overcame hERG liability. Bioavailability was optimised by modulation of physico-chemical properties and physical form to deliver a compound suitable for clinical evaluation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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4. Synthesis and biological evaluation of N-alkylated 8-oxybenz[c]azepine derivatives as selective PPARδ agonists.

Author

Luckhurst CA, Ratcliffe M, Stein L, Furber M, Botterell S, Laughton D, Tomlinson W, Weaver R, Chohan K, and Walding A

Subjects
Anilides chemistry, Anilides pharmacokinetics, Animals, Benzazepines chemical synthesis, Benzazepines pharmacokinetics, Binding Sites, Computer Simulation, Hepatocytes metabolism, Humans, Microsomes, Liver metabolism, PPAR alpha agonists, PPAR alpha metabolism, PPAR delta metabolism, PPAR gamma agonists, PPAR gamma metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Rats, Up-Regulation, Anilides chemical synthesis, Benzazepines chemistry, PPAR delta agonists
Abstract

We describe the discovery of small molecule benzazepine derivatives as agonists of human peroxisome proliferator-activated receptor δ (PPARδ) that displayed excellent selectivity over the PPARα and PPARγ subtypes. Compound 8 displayed good PK in the rat and efficacy in upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) mRNA in human primary myotubes, a biomarker for increased fatty acid oxidation., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Published
2011
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5. Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent, selective PPARδ agonists.

Author

Luckhurst CA, Stein LA, Furber M, Webb N, Ratcliffe MJ, Allenby G, Botterell S, Tomlinson W, Martin B, and Walding A

Subjects
Binding Sites, Catalytic Domain, Computer Simulation, Humans, Indoles chemical synthesis, Indoles pharmacology, PPAR delta metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Structure-Activity Relationship, Tetrahydroisoquinolines chemical synthesis, Tetrahydroisoquinolines pharmacology, Indoles chemistry, PPAR delta agonists, Tetrahydroisoquinolines chemistry
Abstract

Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Published
2011
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