Search

Your search keyword '"Kamlesh Bala"' showing total 4 results
Start Over Author "Kamlesh Bala"
4 results on '"Kamlesh Bala"'

1. Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

Author

Giles Pergl-Wilson, Anna King, Julia Hatto, Henry Danahay, David Andrew Sandham, Mariana Oana Popa, Emily Stanley, Parmjit Bahra, Urs Baettig, Rebecca Butler, Brian Cox, Lightfoot Megan, Christopher J. Page, Alice Young, Paul J. Groot-Kormelink, Trixie Wagner, Swarupa Kulkarni, Glyn Hughes, Edward Charles Hall, David J. Rowlands, Lee Edwards, Atwood K. Cheung, Matthew Spendiff, Tom Sharp, Kamlesh Bala, Stephen Paul Collingwood, Hazel Watson, Julia Koehler, Oliver Ross Steward, Anne-Lise Glotin, Penny Wright, Cara E. Brocklehurst, Ulrike Glaenzel, Ian Nicholls, Richard I. Robinson, Roger J. Taylor, Catherine Howsham, Brian Everatt, Darren Le Grand, Hedaythul Choudhury, Gareth Williams, Emma Budd, Martin Gosling, and Pamela Tranter

Subjects
Cystic Fibrosis, Drug Evaluation, Preclinical, Administration, Oral, Aminopyridines, Cystic Fibrosis Transmembrane Conductance Regulator, Pulmonary disease, 01 natural sciences, Cystic fibrosis, Rats, Sprague-Dawley, Pathogenesis, Pulmonary Disease, Chronic Obstructive, Structure-Activity Relationship, 03 medical and health sciences, Therapeutic approach, Drug Discovery, medicine, Animals, Humans, Clinical efficacy, 030304 developmental biology, 0303 health sciences, COPD, biology, Chemistry, Potentiator, medicine.disease, Cystic fibrosis transmembrane conductance regulator, Rats, respiratory tract diseases, 0104 chemical sciences, Disease Models, Animal, 010404 medicinal & biomolecular chemistry, Solubility, Immunology, biology.protein, Molecular Medicine, Gene Deletion, Half-Life, Protein Binding
Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.

Published
2021
Full Text
View/download PDF

2. Deliberately losing control of C-H activation processes in the design of small-molecule-fragment arrays targeting peroxisomal metabolism

Author

Anthony R. Bradley, Michael Fairhead, Storm Hassell-Hart, Iain J. Day, John Spencer, R. Talon, Kamlesh Bala, S. Velupillai, T. Krojer, Raysa Khan Tareque, Frank von Delft, Robert Felix, Paul Brennan, Kilian Huber, Laura Diaz Saez, and Paul D. Kemmitt

Subjects
Pyridines, Stereochemistry, Fragment-based lead discovery, Chemistry Techniques, Synthetic, Crystallography, X-Ray, Proof of Concept Study, Biochemistry, Catalysis, Small Molecule Libraries, Coordination Complexes, Drug Discovery, Hydrolase, Benzene Derivatives, Humans, Enzyme Inhibitors, Pyrophosphatases, General Pharmacology, Toxicology and Pharmaceutics, Pharmacology, Fragment (computer graphics), Chemistry, Organic Chemistry, Metabolism, Peroxisome, Small molecule, Pyrrolidinones, Drug Design, Feasibility Studies, Molecular Medicine, Selectivity, Palladium, Protein Binding
Abstract

Combined photochemical arylation, "nuisance effect" (SN Ar) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein-ligand structure determination. Reactions were deliberately allowed to run "out of control" in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SN Ar processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.

Published
2020

3. Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases

Author

Brian Cox, David C. Budd, Anna King, Gareth Williams, Nicholas Duggan, Rowan Stringer, Marcus Furegati, Alfred Schmidt, Josef G. Meingassner, Kamlesh Bala, Brian Everatt, Katharine L. Turner, Jennifer Simmons, Cerys Docx, Catherine Leblanc, Gerald Dubois, Frank Kalthoff, Caroline Wilson, Lucy Barker, Karen England, Nicola Arnold, John Westwick, Edward Charles Hall, Bindi Sohal, Jennifer Willis, Heinrich Aschauer, David Andrew Sandham, Rachael Profit, Zarin Brown, Lyndon Nigel Brown, Simon J. Watson, Jodie Manini, Christoph Walker, and Matthew Thomas

Subjects
medicine.drug_class, High-throughput screening, Receptors, Prostaglandin, Clinical Biochemistry, Drug Evaluation, Preclinical, Administration, Oral, Pharmaceutical Science, CHO Cells, Pharmacology, Dermatitis, Contact, Biochemistry, Rats, Sprague-Dawley, Mice, Structure-Activity Relationship, Cricetulus, Th2 Cells, Cricetinae, Drug Discovery, Hypersensitivity, medicine, Animals, Humans, Potency, NVP-QAV680, Receptors, Immunologic, Molecular Biology, Mice, Inbred BALB C, Chemistry, Organic Chemistry, Indolizines, Eosinophil, Receptor antagonist, In vitro, Rats, Bioavailability, Eosinophils, Disease Models, Animal, medicine.anatomical_structure, Lymphocyte activation, Molecular Medicine, Half-Life, Protein Binding
Abstract

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.

Published
2013
Full Text
View/download PDF

4. 7-Azaindole-3-acetic acid derivatives: potent and selective CRTh2 receptor antagonists

Author

Jodie Manini, Claire Adcock, Alfred Schmidt, Zarin Brown, Robin Alec Fairhurst, Rachael Profit, John Reilly, David C. Budd, Caroline Wilson, Simon J. Watson, Brian Cox, Kamlesh Bala, Jennifer Willis, Lucy Barker, Markus Furegati, David Andrew Sandham, Katharine L. Turner, Rowan Stringer, Catherine Leblanc, Gareth Williams, and Gerald Dubois

Subjects
medicine.drug_class, Pyridines, Clinical Biochemistry, Receptors, Prostaglandin, Anti-Inflammatory Agents, Pharmaceutical Science, Administration, Oral, Acetates, Biochemistry, Permeability, Acetic acid, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, medicine, Structure–activity relationship, Potency, Animals, Humans, Receptors, Immunologic, Receptor, Molecular Biology, Whole blood, Organic Chemistry, Antagonist, Receptor antagonist, Bioavailability, Rats, Eosinophils, chemistry, Microsomes, Liver, Molecular Medicine
Abstract

High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.

Published
2009

Catalog

Books, media, physical & digital resources
See catalog results