Author: "Medhurst SJ" / Publisher: elsevier science ltd - Searchworks@Jio Institute Digital Library Search Results

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Start Over Author "Medhurst SJ" Publisher elsevier science ltd

Author: Abberley L, Bebius A, Beswick PJ, Billinton A, Collis KL, Dean DK, Fonfria E, Gleave RJ, Medhurst SJ, Michel AD, Moses AP, Patel S, Roman SA, Scoccitti T, Smith B, Steadman JG, and Walter DS
Subjects: Administration, Oral, Animals, Biological Availability, Half-Life, Haplorhini, Imidazolines administration & dosage, Imidazolines chemistry, Imidazolines pharmacokinetics, Purinergic Antagonists administration & dosage, Purinergic Antagonists chemistry, Purinergic Antagonists pharmacokinetics, Rats, Imidazolines pharmacology, Purinergic Antagonists pharmacology, Receptors, Purinergic P2X7 drug effects
Abstract: A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
Published: 2010
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Author: Abdi MH, Beswick PJ, Billinton A, Chambers LJ, Charlton A, Collins SD, Collis KL, Dean DK, Fonfria E, Gleave RJ, Lejeune CL, Livermore DG, Medhurst SJ, Michel AD, Moses AP, Page L, Patel S, Roman SA, Senger S, Slingsby B, Steadman JG, Stevens AJ, and Walter DS
Subjects: Amides chemistry, Drug Discovery, Models, Molecular, Purinergic P2 Receptor Antagonists chemistry, Structure-Activity Relationship, Amides pharmacology, Purinergic P2 Receptor Antagonists pharmacology, Pyrrolidonecarboxylic Acid chemistry, Receptors, Purinergic P2X7 drug effects
Abstract: A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies., (Copyright 2010 Elsevier Ltd. All rights reserved.)
Published: 2010
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Author: Beswick PJ, Billinton A, Chambers LJ, Dean DK, Fonfria E, Gleave RJ, Medhurst SJ, Michel AD, Moses AP, Patel S, Roman SA, Roomans S, Senger S, Stevens AJ, and Walter DS
Subjects: Acetamides chemical synthesis, Acetamides therapeutic use, Administration, Oral, Animals, Disease Models, Animal, Humans, Pain drug therapy, Pyrazoles chemical synthesis, Rats, Receptors, Purinergic P2X7 metabolism, Structure-Activity Relationship, Acetamides chemistry, Purinergic P2X Receptor Antagonists, Pyrazoles chemistry
Abstract: Structure-activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund's adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537]., (Copyright 2010 Elsevier Ltd. All rights reserved.)
Published: 2010
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Author: Westaway SM, Thompson M, Rami HK, Stemp G, Trouw LS, Mitchell DJ, Seal JT, Medhurst SJ, Lappin SC, Biggs J, Wright J, Arpino S, Jerman JC, Cryan JE, Holland V, Winborn KY, Coleman T, Stevens AJ, Davis JB, and Gunthorpe MJ
Subjects: Administration, Oral, Animals, Benzothiazoles pharmacology, Capsaicin chemistry, Cell Line, Drug Design, Guinea Pigs, Humans, Inflammation, Inhibitory Concentration 50, Models, Chemical, Niacinamide chemistry, Niacinamide pharmacology, Rats, Benzothiazoles chemical synthesis, Chemistry, Pharmaceutical methods, Niacinamide analogs & derivatives, Niacinamide chemical synthesis, TRPV Cation Channels antagonists & inhibitors, TRPV Cation Channels chemistry
Abstract: 6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.
Published: 2008
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Author: Westaway SM, Chung YK, Davis JB, Holland V, Jerman JC, Medhurst SJ, Rami HK, Stemp G, Stevens AJ, Thompson M, Winborn KY, and Wright J
Subjects: Animals, Benzamides chemical synthesis, Capsaicin pharmacology, Guinea Pigs, Humans, Isoquinolines chemical synthesis, Liver drug effects, Liver metabolism, Molecular Structure, Quinolines chemical synthesis, Rats, Structure-Activity Relationship, TRPV Cation Channels metabolism, Benzamides chemistry, Benzamides pharmacology, Isoquinolines chemistry, Isoquinolines pharmacology, Quinolines chemistry, Quinolines pharmacology, TRPV Cation Channels antagonists & inhibitors
Abstract: Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.
Published: 2006
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