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Michael G N Russell,
Robert W Carling,
Leslie J Street,
David J Hallett,
Simon Goodacre,
Elena Mezzogori,
Michael Reader,
Susan M Cook, Frances A Bromidge,
Robert Newman, [......],
Pushpindar Ferris,
Jo Stanley,
Rachael Lincoln,
Spencer J Tye,
Wayne F A Sheppard,
Bindi Sohal,
Andrew Pike,
Maria Dominguez,
John R Atack,
José L Castro
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ABSTRACT: The identification of a series of imidazo[1,2-b][1,2,4]triazines with high affinity and functional selectivity for the GABA(A) alpha3-containing receptor subtype is described, leading to the identification of a clinical candidate, 11. Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models.
Journal of Medicinal Chemistry 03/2006; 49(4):1235-8. · 5.25 Impact Factor
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Michael G N Russell,
Robert W Carling,
John R Atack, Frances A Bromidge,
Susan M Cook,
Peter Hunt,
Catherine Isted,
Matt Lucas,
Ruth M McKernan,
Andrew Mitchinson,
Kevin W Moore,
Robert Narquizian,
Alison J Macaulay,
David Thomas,
Sally-Anne Thompson,
Keith A Wafford,
José L Castro
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ABSTRACT: We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the alpha(3) receptor subtype with 5-fold selectivity in binding affinity over alpha(1). This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the alpha(3) subtype over the alpha(1) subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at alpha(1) and antagonism at alpha(3) (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the alpha(3) subtype over the alpha(1) subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
Journal of Medicinal Chemistry 04/2005; 48(5):1367-83. · 5.25 Impact Factor
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Leslie J Street,
Francine Sternfeld,
Richard A Jelley,
Austin J Reeve,
Robert W Carling,
Kevin W Moore,
Ruth M McKernan,
Bindi Sohal,
Susan Cook,
Andrew Pike,
Gerard R Dawson, Frances A Bromidge,
Keith A Wafford,
Guy R Seabrook,
Sally A Thompson,
George Marshall,
Goplan V Pillai,
José L Castro,
John R Atack,
Angus M MacLeod
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ABSTRACT: The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABA(A)alpha5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of alpha5- over alpha1-, alpha2-, and alpha3-containing GABA(A) receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABA(A)alpha5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABA(A)alpha5 subtype with functional selectivity over the other GABA(A) receptor subtypes and good oral bioavailability.
Journal of Medicinal Chemistry 08/2004; 47(14):3642-57. · 5.25 Impact Factor
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Leslie J. Street,
Francine Sternfeld,
Richard A. Jelley,
Austin J. Reeve,
Robert W. Carling,
Kevin W. Moore,
Ruth M. McKernan,
Bindi Sohal,
Susan Cook,
Andrew Pike,
Gerard R. Dawson, Frances A. Bromidge,
Keith A. Wafford,
Guy R. Seabrook,
Sally A. Thompson,
George Marshall,
Goplan V. Pillai,
José L. Castro,
John R. Atack,
Angus M. MacLeod
[show abstract]
[hide abstract]
ABSTRACT: The identification of a novel series of 7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines as GABAAα5 inverse agonists, which have both binding and functional (efficacy) selectivity for the benzodiazepine binding site of α5- over α1-, α2-, and α3-containing GABAA receptor subtypes, is described. Binding selectivity was determined to a large part by the degree of planarity of the fused ring system whereas functional selectivity was dependent on the nature of the heterocycle at the 3-position of the triazolopyridazine ring. 3-Furan and 5-methylisoxazole were shown to be optimal for GABAAα5 functional selectvity. 3-(5-Methylisoxazol-3-yl)-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (43) was identified as a full inverse agonist at the GABAAα5 subtype with functional selectivity over the other GABAA receptor subtypes and good oral bioavailability.
05/2004;
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Ian Collins,
Christopher Moyes,
William B Davey,
Michael Rowley, Frances A Bromidge,
Kathleen Quirk,
John R Atack,
Ruth M McKernan,
Sally-Ann Thompson,
Keith Wafford,
Gerard R Dawson,
Andrew Pike,
Bindi Sohal,
Nancy N Tsou,
Richard G Ball,
José L Castro
[show abstract]
[hide abstract]
ABSTRACT: A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human gamma-aminobutyric acid (GABA(A)) receptor ion channels, low binding selectivity for alpha 2- and/or alpha 3- over alpha 1-containing GABA(A) receptor subtypes and high binding selectivity over alpha 5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S.O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for alpha 2 and/or alpha 3 GABA(A) receptor subtypes over alpha1 was observed in several of these compounds in electrophysiological assays. Furthermore, an alpha 3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an alpha 2/alpha 3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.
Journal of Medicinal Chemistry 05/2002; 45(9):1887-900. · 5.25 Impact Factor
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Mark S Chambers,
John R Atack, Frances A Bromidge,
Howard B Broughton,
Susan Cook,
Gerard R Dawson,
Sarah C Hobbs,
Karen A Maubach,
Austin J Reeve,
Guy R Seabrook,
Keith Wafford,
Angus M MacLeod
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ABSTRACT: Nonselective inverse agonists at the benzodiazepine binding site on the GABA-A chloride ion channel enhance cognitive performance in animals but cannot be used in the treatment of cognitive disorders because of anxiogenic and convulsant side effects. We have identified a novel series of GABA-A alpha5 receptor ligands during our search for alpha5 receptor inverse agonists as potential cognition enhancers. In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A alpha5 inverse agonist.
Journal of Medicinal Chemistry 04/2002; 45(6):1176-9. · 5.25 Impact Factor
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Ian Collins,
Christopher Moyes,
William B. Davey,
Michael Rowley, Frances A. Bromidge,
Kathleen Quirk,
John R. Atack,
Ruth M. McKernan,
Sally-Ann Thompson,
Keith Wafford,
Gerard R. Dawson,
Andrew Pike,
Bindi Sohal,
Nancy N. Tsou,
Richard G. Ball,
José L. Castro
[show abstract]
[hide abstract]
ABSTRACT: A novel series of 3-heteroaryl-5,6-bis(aryl)-1-methyl-2-pyridones were developed with high affinity for the benzodiazepine (BZ) binding site of human γ-aminobutyric acid (GABAA) receptor ion channels, low binding selectivity for α2- and/or α3- over α1-containing GABAA receptor subtypes and high binding selectivity over α5 subtypes. High affinity appeared to be associated with a coplanar conformation of the pyridone and sulfur-containing 3-heteroaryl rings resulting from an attractive S...O intramolecular interaction. Functional selectivity (i.e., selective efficacy) for α2 and/or α3 GABAA receptor subtypes over α1 was observed in several of these compounds in electrophysiological assays. Furthermore, an α3 subtype selective inverse agonist was proconvulsant and anxiogenic in rodents while an α2/α3 subtype selective partial agonist was anticonvulsant and anxiolytic, supporting the hypothesis that subtype selective BZ site agonists may provide new anxiolytic therapies.
03/2002;
