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5 results on '"Teobald B"'

1. Antagonists of the Platelet P<INF>2T</INF><INF></INF> Receptor:  A Novel Approach to Antithrombotic Therapy

Author

Ingall, A. H., Dixon, J., Bailey, A., Coombs, M. E., Cox, D., McInally, J. I., Hunt, S. F., Kindon, N. D., Teobald, B. J., Willis, P. A., Humphries, R. G., Leff, P., Clegg, J. A., Smith, J. A., and Tomlinson, W.

Abstract

The platelet P2T receptor plays a major role in platelet aggregation, and its antagonists are predicted to have significant therapeutic potential as antithrombotic agents. We have explored analogues of adenosine triphosphate (ATP), which is a weak, nonselective but competitive P2T receptor antagonist. Modification of the polyphosphate side chain to prevent breakdown to the agonist adenosine diphosphate (ADP) and substitution of the adenine moiety to enhance affinity and selectivity for the P2T receptor led to the identification of 10e (AR-C67085MX), having an IC50 of 2.5 nM against ADP-induced aggregation of human platelets. Compound 10e was the first very potent antagonist of the P2T receptor, with a selectivity for that subtype of the P2 receptor family of >1000-fold. Further modification of the structure produced compound 10l (AR-C69931MX) having an IC50 of 0.4 nM. In vivo, at maximally effective antithrombotic doses, there is little prolongation of bleeding time (1.4-fold), which is in marked contrast to the 5−6-fold found with GPIIb/IIIa antagonists.

Published
1999

2. From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Author

Brown AJH, Bradley SJ, Marshall FH, Brown GA, Bennett KA, Brown J, Cansfield JE, Cross DM, de Graaf C, Hudson BD, Dwomoh L, Dias JM, Errey JC, Hurrell E, Liptrot J, Mattedi G, Molloy C, Nathan PJ, Okrasa K, Osborne G, Patel JC, Pickworth M, Robertson N, Shahabi S, Bundgaard C, Phillips K, Broad LM, Goonawardena AV, Morairty SR, Browning M, Perini F, Dawson GR, Deakin JFW, Smith RT, Sexton PM, Warneck J, Vinson M, Tasker T, Tehan BG, Teobald B, Christopoulos A, Langmead CJ, Jazayeri A, Cooke RM, Rucktooa P, Congreve MS, Weir M, and Tobin AB

Subjects
Aged, Aged, 80 and over, Aging pathology, Alzheimer Disease complications, Alzheimer Disease diagnostic imaging, Alzheimer Disease pathology, Amino Acid Sequence, Animals, Blood Pressure drug effects, CHO Cells, Cholinesterase Inhibitors pharmacology, Cricetulus, Crystallization, Disease Models, Animal, Dogs, Donepezil pharmacology, Electroencephalography, Female, HEK293 Cells, Heart Rate drug effects, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Molecular Dynamics Simulation, Nerve Degeneration complications, Nerve Degeneration pathology, Primates, Rats, Receptor, Muscarinic M1 chemistry, Signal Transduction, Structural Homology, Protein, Mice, Alzheimer Disease drug therapy, Drug Design, Receptor, Muscarinic M1 agonists
Abstract

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic., Competing Interests: Declaration of interests T.T. and M.W. are shareholders and board members of Sosei Heptares. The authors A.J.H.B., G.A.B., K.A.B., J.B., J.E.C., M.S.C., R.M.C., J.C.E., E.H., A.J., C.J.L., J.L., F.H.M., P.J.N., K.O., G.O., J.C.P., M.P., N.R., P.R., B.G.T., R.T.S., C.d.G., G.M., and B.T. are or have been employees of Heptares Therapeutics and are shareholders of Sosei Heptares., (Copyright © 2021. Published by Elsevier Inc.)

Published
2021
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3. Discovery of AZD-2098 and AZD-1678, Two Potent and Bioavailable CCR4 Receptor Antagonists.

Author

Kindon N, Andrews G, Baxter A, Cheshire D, Hemsley P, Johnson T, Liu YZ, McGinnity D, McHale M, Mete A, Reuberson J, Roberts B, Steele J, Teobald B, Unitt J, Vaughan D, Walters I, and Stocks MJ

Abstract

N -(5-Bromo-3-methoxypyrazin-2-yl)-5-chlorothiophene-2-sulfonamide 1 was identified as a hit in a CCR4 receptor antagonist high-throughput screen (HTS) of a subset of the AstraZeneca compound bank. As a hit with a lead-like profile, it was an excellent starting point for a CCR4 receptor antagonist program and enabled the rapid progression through the Lead Identification and Lead Optimization phases resulting in the discovery of two bioavailable CCR4 receptor antagonist candidate drugs.

Published
2017
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4. Lead optimisation of pyrazoles as novel FPR1 antagonists.

Author

Morley AD, King S, Roberts B, Lever S, Teobald B, Fisher A, Cook T, Parker B, Wenlock M, Phillips C, and Grime K

Subjects
Animals, Chemistry, Pharmaceutical methods, Chemistry, Physical methods, Drug Design, Hepatocytes cytology, Humans, Inhibitory Concentration 50, Male, Microsomes, Liver metabolism, Models, Chemical, Rats, Rats, Sprague-Dawley, Receptors, Formyl Peptide chemistry, Pyrazoles chemical synthesis, Pyrazoles pharmacology, Receptors, Formyl Peptide antagonists & inhibitors
Abstract

Optimisation of a series of pyrazole inhibitors of the human FPR1 receptor has been achieved. The use of an in vitro media loss assay was utilised to identify sub-series with more robust DMPK profiles. These were subsequently improved to generate analogues with attractive overall profiles., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2012
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5. The discovery of AZD9164, a novel muscarinic M3 antagonist.

Author

Mete A, Bowers K, Chevalier E, Donald DK, Edwards H, Escott KJ, Ford R, Grime K, Millichip I, Teobald B, and Russell V

Subjects
Blood Proteins metabolism, Drug Evaluation, Preclinical, Humans, Muscarinic Antagonists pharmacology, Muscarinic Antagonists therapeutic use, Piperidines pharmacology, Piperidines therapeutic use, Protein Binding, Pulmonary Disease, Chronic Obstructive drug therapy, Quinuclidines pharmacology, Quinuclidines therapeutic use, Receptor, Muscarinic M3 metabolism, Structure-Activity Relationship, Muscarinic Antagonists chemistry, Piperidines chemistry, Quinuclidines chemistry, Receptor, Muscarinic M3 agonists
Abstract

The optimization of a new series of muscarinic M(3) antagonists is described, leading to the identification of AZD9164 which was progressed into the clinic for evaluation of its potential as a treatment for COPD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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