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Your search keyword '"Nicholas John Newcombe"' showing total 3 results
Start Over Author "Nicholas John Newcombe" Journal journal of medicinal chemistry
3 results on '"Nicholas John Newcombe"'

1. Identification, Optimization, and Pharmacology of Acylurea GHS-R1a Inverse Agonists

Author

Suzanne S. Bowker, Clive Green, Graeme R. Robb, Stephen Stokes, Nathaniel G. Martin, Anne Ertan, David G.A. Morgan, Christopher Sheldon, Alexander G. Dossetter, Robert D. M. Davies, David S. Clarke, Alastair J. H. Brown, William McCoull, Helen Pointon, Jane E. Moore, Mark L. Fenwick, Nicholas John Newcombe, Claire Newton, Jane L. Holmes, David J. Masters, Peter Barton, and Jennifer Cameron

Subjects
Models, Molecular, medicine.medical_specialty, Drug Inverse Agonism, High-throughput screening, Pharmacology, Partial agonist, Structure-Activity Relationship, chemistry.chemical_compound, Internal medicine, Drug Discovery, medicine, Humans, Urea, Inverse agonist, Structure–activity relationship, Receptors, Ghrelin, Receptor, Dose-Response Relationship, Drug, Molecular Structure, digestive, oral, and skin physiology, Endocrinology, chemistry, Molecular Medicine, Ghrelin, Penetrant (biochemical), hormones, hormone substitutes, and hormone antagonists
Abstract

Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.

Published
2014

2. Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid (AZD4017)

Author

James S. Scott, Nidhal Selmi, Joanne deSchoolmeester, Suzanne S. Bowker, Amanda Rees, Rachel M. Mayers, Derek Ogg, Paul Schofield, Elaine Kilgour, John G. Swales, Stefan Gerhardt, William McCoull, Martin J. Packer, David J. Hargreaves, Nicholas John Newcombe, John Revill, Adele Lloyd, and Paul Robert Owen Whittamore

Subjects
Male, Models, Molecular, Niacinamide, Stereochemistry, Protein Conformation, Carboxylic acid, Administration, Oral, Biological Availability, Substrate Specificity, Acetic acid, chemistry.chemical_compound, Inhibitory Concentration 50, Mice, Dogs, Piperidines, 11β-hydroxysteroid dehydrogenase type 1, Amide, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Drug Discovery, Potency, Animals, Humans, Enzyme Inhibitors, chemistry.chemical_classification, biology, Chemistry, Drug discovery, Bioavailability, Rats, Nicotinic agonist, Biochemistry, biology.protein, Molecular Medicine, hormones, hormone substitutes, and hormone antagonists
Abstract

Inhibition of 11β-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11β-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.

Published
2012

3. Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas

Author

Siân Rowsell, Shannon Ready, James W. Janetka, Dongfang Liu, Paul Lyne, Jason Breed, Patrick Brassil, Nicholas John Newcombe, Jon Read, Susan Ashwell, Dingwei Yu, Mei Su, Dorin Toader, Yan Yu, Melissa Vasbinder, Vibha Oza, Lynsie Almeida, Chun Deng, Sonya Zabludoff, Martin Pass, Stephanos Ioannidis, Candice Horn, Michael Grondine, Thomas Gero, and Yafeng Xue

Subjects
Models, Molecular, animal structures, DNA repair, Stereochemistry, DNA damage, medicine.drug_class, High-throughput screening, Carboxamide, Antineoplastic Agents, Thiophenes, Crystallography, X-Ray, Irinotecan, environment and public health, Deoxycytidine, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Drug Discovery, Ribose, medicine, Structure–activity relationship, Animals, Urea, CHEK1, Protein Kinase Inhibitors, Binding Sites, Molecular Structure, Chemistry, Kinase, Drug Synergism, Stereoisomerism, Xenograft Model Antitumor Assays, Gemcitabine, High-Throughput Screening Assays, Rats, enzymes and coenzymes (carbohydrates), Drug Design, Checkpoint Kinase 1, Molecular Medicine, Camptothecin, biological phenomena, cell phenomena, and immunity, Protein Kinases, DNA Damage
Abstract

Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.

Published
2012

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