Paul Martin Gore
GlaxoSmithKline
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Featured researches published by Paul Martin Gore.
Tetrahedron Letters | 1995
Jeremy C. Prodger; Mark James Bamford; Paul Martin Gore; Duncan S. Holmes; Victoria Saez; Peter Ward
Abstract Two different strategies have been developed in order to synthesise an analogue and potential mimic of sialyl Lewis X that incorporates a carboxymethyl group and a C 2 -symmetric 2,3-butanediol unit as replacements for the sialic acid and the N-acetylglucosamine residues respectively.
Journal of Medicinal Chemistry | 2011
Panayiotis A. Procopiou; Christopher Browning; Jennifer M. Buckley; Kenneth L. Clark; Lise Fechner; Paul Martin Gore; Ashley Paul Hancock; Simon Teanby Hodgson; Duncan S. Holmes; Michael Kranz; Brian Edgar Looker; Karen Morriss; Daniel L. Parton; Linda J. Russell; Robert J. Slack; Steven L. Sollis; Sadie Vile; Clarissa J. Watts
A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.
Organic and Biomolecular Chemistry | 2003
Paul J. Dransfield; Paul Martin Gore; Ivan Prokes; Michael Shipman; Alexandra M. Z. Slawin
The synthesis of 3,4,6-tri-O-acetyl imino D-glucal 2 from D-glucal is reported. This imino glycal participates in a variety of Lewis acid mediated carbon-carbon bond forming reactions by allylic displacement of the C-3 acetate group by added nucleophiles. Allyl silanes, trimethylsilyl enol ethers, alkenes and dialkyl zinc reagents serve as suitable reaction partners. In all the cases studied, the beta-anomer is predominant. Using imino glycal 8, epimeric at C-5, it is established that the configuration at C-5 of the piperidine ring plays a major role in controlling the stereochemical outcome. These results are rationalised by invoking the intermediacy of a conjugated N-acyliminium ion. A short stereocontrolled synthesis of (+)-deoxoprosophylline is achieved using this chemistry. Additionally, imino glucal 2 is transformed into bromo piperidine 16, whose X-ray crystal structure is determined. Bromide 16 participates in palladium catalysed Stille and Suzuki cross-couplings allowing access to C-2 substituted imino sugars 17 and 18. In other studies, imino sugar C-glycosides 21 and 22 are made by combining the Lewis acid mediated carbon-carbon bond forming reactions with stereospecific dihydroxylations.
Bioorganic & Medicinal Chemistry Letters | 1994
Anthony William James Cooper; Hilary S. Adams; Richard Bell; Paul Martin Gore; Andrew B. McElroy; John M. Pritchard; Paul W. Smith; Peter Ward
Abstract Optimisation of NK 2 receptor affinity in a series of sulfur derivatives resulted in the identification of Highly potent 5-fluoroindol-3-ylethyl[4-(phenylsulfinyl methyl])piperidines. Further structure activity analysis led to GR 159897 an NK 2 receptor antagonist which potently blocks agonist-induced bronchoconstriction in the guinea-pig when administered by peripheral and oral routes.
Bioorganic & Medicinal Chemistry | 2012
Panayiotis A. Procopiou; Christopher Browning; Paul Martin Gore; Sean M. Lynn; Stephen A. Richards; Robert J. Slack; Steven L. Sollis
5-Aza, 6-aza, 7-aza and 8-aza-phthalazinone, and 5,8-diazaphthalazinone templates were synthesised by stereoselective routes starting from the appropriate pyridine/pyrazine dicarboxylic acids by activation with CDI, reaction with 4-chlorophenyl acetate ester enolate to give a β-ketoester, which was hydrolysed, and decarboxylated. The resulting ketone was condensed with hydrazine to form the azaphthalazinone core. The azaphthalazinone cores were alkylated with N-Boc-D-prolinol at N-2 by Mitsunobu reaction, de-protected, and then alkylated at the pyrrolidine nitrogen to provide the target H(1) receptor antagonists. All four mono-azaphthalazinone series had higher affinity (pK(i)) for the human H(1) receptor than azelastine, but were not as potent as the parent non-aza phthalazinone. The 5,8-diazaphthalazinone was equipotent with azelastine. The least potent series were the 7-azaphthalazinones, whereas the 5-azaphthalazinones were the most lipophilic. The more hydrophilic series were the 8-aza series. Replacement of the N-methyl substituent on the pyrrolidine with the n-butyl group caused an increase in potency (pA(2)) and a corresponding increase in lipophilicity. Introduction of a β-ether oxygen in the n-butyl analogues (2-methoxyethyl group) decreased the H(1) pA(2) slightly, and increased the selectivity against hERG. The duration of action in vitro was longer in the 6-azaphthalazinone series. The more potent and selective 6-azaphthalazinone core was used to append an H(3) receptor antagonist fragment, and to convert the series into the long acting single-ligand, dual H(1) H(3) receptor antagonist 44. The pharmacological profile of 44 was very similar to our intranasal clinical candidate 1.
Chemical Communications | 2002
Paul J. Dransfield; Paul Martin Gore; Michael Shipman; Alexandra M. Z. Slawin
Tri-O-acetyl imino glucal 2 is readily made and shown to undergo a variety of Lewis acid mediated carbon-carbon bond forming reactions at C-1 of the piperidine nucleus. In all the reactions studied, the beta-anomer is predominant.
Bioorganic & Medicinal Chemistry Letters | 2016
Panayiotis A. Procopiou; Rachael Anne Ancliff; Paul Martin Gore; Ashley Paul Hancock; Simon Teanby Hodgson; Duncan S. Holmes; Steven Philip Keeling; Brian Edgar Looker; Nigel A. Parr; James E. Rowedder; Robert J. Slack
A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.
ACS Medicinal Chemistry Letters | 2017
Panayiotis A. Procopiou; Alison J. Ford; Paul Martin Gore; Brian Edgar Looker; Simon Teanby Hodgson; Duncan S. Holmes; Sadie Vile; Kenneth L. Clark; Ken Saunders; Robert J. Slack; James E. Rowedder; Clarissa J. Watts
The synthesis of potent amide-containing phthalazinone H1 histamine receptor antagonists is described. Three analogues 3e, 3g, and 9g were equipotent with azelastine and were longer-acting in vitro. Amide 3g had low oral bioavailability, low brain-penetration, high metabolic clearance, and long duration of action in vivo, and it was suitable for once-daily dosing intranasally, with a predicted dose for humans of approximately 0.5 mg per day.
Bioorganic & Medicinal Chemistry Letters | 2017
Panayiotis A. Procopiou; Alison J. Ford; Paul Martin Gore; Ashley Paul Hancock; Simon Teanby Hodgson; Duncan S. Holmes; Brian Edgar Looker; Sadie Vile; Kenneth L. Clark; Ken Saunders; Robert J. Slack; Clarissa J. Watts
A series of potent, selective and long-acting quinoline-based sulfonamide human H1 histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H1 receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine.
Archive | 2001
Rachael Anne Ancliff; Caroline Mary Cook; Colin David Eldred; Paul Martin Gore; Lee Andrew Harrison; Simon Teanby Hodgson; Duncan Bruce Judd; Suzanne Elaine Keeling; Xiao Qing Lewell; Graeme Michael Robertson; Stephen Swanson