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4 results on '"Natalie Wellaway"'

1. Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase

Author

Stéphane Sautet, Emilie Jigorel, Nicolas Faucher, Jamel Meslamani, Lara Kathryn Leister, Pascal Grondin, Julie A. Cox, Bryan W. King, Pamela Nassau, Gemma Victoria White, Brad J. Geddes, Alain Claude-Marie Daugan, Helen H. Sun, Michael T. Ouellette, Pauline Lamoureux, Elizabeth J. Rivera, Scott B. Berger, James H. Thorpe, Philip A. Harris, J. Mosley, Susan E. Hutchinson, Frédéric Donche, John Bertin, Sandra J. Hoffman, Natalie Wellaway, Patrick M. Eidam, Paris Ward, Florent Potvain, Clark A. Sehon, Sebastien Andre Campos, Robert W. Marquis, Peter J. Gough, Mukesh K. Mahajan, Veronique Beneton, Jae U. Jeong, Michelle C. Schaeffer, John D. Lich, Allison M. Beal, Rakesh Nagilla, James Michael Woolven, Bonnie L. Hoffman, Anderson Niall Andrew, Marie-Hélène Fouchet, Deepak Bandyopadhyay, Carol A. Capriotti, Rachel D. Totoritis, Joshua N. Finger, Kishore K. Pasikanti, David D. Wisnoski, Sze-Ling Ng, Nino Campobasso, Nicolas George, and Michael Reilly

Subjects
Models, Molecular, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Necroptosis, Biological Availability, Inflammation, Pharmacology, 01 natural sciences, Cell Line, Mice, Structure-Activity Relationship, 03 medical and health sciences, In vivo, Psoriasis, Drug Discovery, medicine, Animals, Humans, Structure–activity relationship, Enzyme Inhibitors, 030304 developmental biology, 0303 health sciences, Kinase, Chemistry, RNA-Binding Proteins, Haplorhini, medicine.disease, Ulcerative colitis, High-Throughput Screening Assays, Rats, 0104 chemical sciences, Mice, Inbred C57BL, Nuclear Pore Complex Proteins, 010404 medicinal & biomolecular chemistry, Drug Design, Rheumatoid arthritis, Chronic Disease, Pyrazoles, Molecular Medicine, medicine.symptom, Retinitis Pigmentosa
Abstract

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.

Published
2019

2. Evolution of a Novel, Orally Bioavailable Series of PI3Kδ Inhibitors from an Inhaled Lead for the Treatment of Respiratory Disease

Author

Sorif Uddin, Graham G. A. Inglis, Paul Rowland, Christopher J. Tame, Christopher N. Luscombe, Nick Barton, Natalie Wellaway, Anthony William James Cooper, Josie Morrell, Giovanni Vitulli, David Perez, Augustin Amour, Simon Peace, and Craig Jamieson

Subjects
Male, Models, Molecular, 0301 basic medicine, Respiratory Tract Diseases, Biological Availability, Pharmacology, Rats sprague dawley, RS, Rats, Sprague-Dawley, Structure-Activity Relationship, 03 medical and health sciences, In vivo, Administration, Inhalation, Drug Discovery, medicine, Animals, Protein Kinase Inhibitors, Phosphoinositide-3 Kinase Inhibitors, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Respiratory disease, medicine.disease, Rats, Bioavailability, Class Ia Phosphatidylinositol 3-Kinase, 030104 developmental biology, Molecular Medicine, Biological availability
Abstract

A four step process of high quality modelling of existing data, deconstruction, identification of replacement cores and an innovative synthetic re-growth strategy led to the rapid discovery of a novel oral series of PI3K δ inhibitors with promising selectivity and excellent in vivo characteristics.

Published
2016

4. A practical drug discovery project at the undergraduate level

Author

Diane M. Coe, Vipulkumar Kantibhai Patel, Stephen Swanson, Ian B. Campbell, Simon J. F. Macdonald, John Liddle, Gail Fisher, M. Jonathan Fray, Ian Churcher, Graham G. A. Inglis, Ian Robert Baldwin, Natalie Wellaway, Anthony William James Cooper, Henry Anderson Kelly, Nick Barton, Jack A. Brown, Aoife C. Maxwell, and Andrew P. Craven

Subjects
Pharmacology, Models, Molecular, Medical education, Drug Industry, Drug discovery, business.industry, undergraduate research project, asthma, kinase, PI3K delta, thienopyrimidines, Chemistry, Pharmaceutical, education, Learning experience, Solubility, Drug Design, Aqueous solubility, Drug Discovery, Medicine, Humans, Curriculum, Enzyme Inhibitors, business, Simulation, Phosphoinositide-3 Kinase Inhibitors
Abstract

A practical drug discovery project for third-year undergraduates is described. No previous knowledge of medicinal chemistry is assumed. Initial lecture-workshops cover the basic principles; then students are asked to improve the profile of a weakly potent, poorly soluble PI3K inhibitor (1). Compound array design, molecular modelling and screening data analysis are followed by laboratory work in which each student, as part of a team, attempts to synthesise at least two target compounds. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. Forty-eight target compounds have been prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and 10-fold, respectively.

Published
2013

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