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Featured researches published by Thomas J. Brown.


Bioorganic & Medicinal Chemistry Letters | 1998

Identification of a non peptidic rantes antagonist

Colin P. Bright; Thomas J. Brown; Paul Joseph Cox; Frank Halley; Peter M. Lockey; Iain Mcfarlane Mclay; Una M. Moore; Barry Porter; Robert J. Williams

A series of phenothiazines demonstrating inhibition of RANTES binding to THP-1 cell membranes has been identified. The lead compound RP23618 (IC50 = 3 microM) was found to inhibit specific binding of 125I-RANTES, but not 125I-MCP-1 to THP-1 cell membranes and furthermore to antagonize RANTES, but not MCP-1-induced chemotaxis of THP-1 cells.


European Journal of Medicinal Chemistry | 1997

Selective endothelin A receptor ligands. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives

Peter Charles Astles; Thomas J. Brown; C. M. Handscombe; M. F. Harper; Neil Victor Harris; Richard A. Lewis; Peter M. Lockey; Clive Mccarthy; Iain Mcfarlane Mclay; Barry Porter; Alan Geoffrey Roach; Christopher Smith; Roger John Aitchison Walsh

Summary This paper describes the discovery of a new non-peptide endothelin A (ETA) selective ligand, 2,4-dibenzyloxybenzoic acid 3, which inhibits the binding of [125I]ET-1 to ETA receptors with an IC50 of 9 μM (ET-1 = endothelin-1). Optimisation of 3 resulted in compound 52 which had an IC50 of 1 μM. One of the analogues of 3, compound 15, was examined in a functional assay and shown to antagonise ET-1-induced contraction of rat aorta. The identification of 3 was made through the application of ChemDBS-3D searching of our corporate database. The 3D query, using an aromatic ring to a carboxylic acid group separated by 10.2 ± 1.1 A, was derived from an examination of common pharmacophoric distances found in the low energy conformations of two known ETA antagonists, the cyclic pentapeptide BQ 123 1 and myriceron caffeoyl ester 2.


Bioorganic & Medicinal Chemistry Letters | 1997

New non peptidic C5a receptor antagonists

Peter Charles Astles; Thomas J. Brown; Paul Joseph Cox; Frank Halley; Peter M. Lockey; Clive Mccarthy; Iain Mcfarlane Mclay; Tahir N. Majid; Andrew David Morley; Barry Porter; Andrew J. Ratcliffe; Roger John Aitchison Walsh

Abstract A series of phenylguanidines which bind to the C5a receptor has been developed. The lead compound 1 (IC50=30μM), discovered through random screening, has been modified to provide 32 (RPR121154) with submicromolar activity. This compound was shown to further elicit functional antagonism in a human neutrophil C5a stimulated respiratory burst assay.


Journal of Cardiovascular Pharmacology | 1995

Effect of endothelin antagonists with or without BQ 788 on ET-1 responses in pithed rats.

Carol A. Sargent; R. Brazdil; D. A. Flynn; Thomas J. Brown; Alan Geoffrey Roach

Summary: The overall effects of endothelin-1 (ET-1) on blood pressure are caused by a composite activation of constrictor ETA and ETB receptors and dilator ETB receptors. Therefore, it is difficult to accurately compare the ETA activity of selective ETA receptor antagonists (BQ 123 and BMS 182874) with mixed ETA/ETB antagonists (SB 209670 and bosentan) on the cumulative dose-response curve to ET-1. The development of a selective ETB antagonist (BQ 788), which inhibits both the dilator and constrictor ETB receptors, offered the opportunity to investigate the role of ETB receptors in the response to exogenous ET-1 in the pithed rat. BQ 788 (3 mg/kg) resulted in an eightfold leftward shift in the ET-1 doseresponse curve, suggesting a significant involvement of ETB dilator receptors. In the absence or presence of BQ 788, each ET antagonist evoked a rightward shift from vehicle. With the exception of BMS 182874, BQ 788 increased the magnitude of the shifts. Furthermore, the profile of the shifts changed from nonparallel to parallel in the presence of BQ 788. The inclusion of BQ 788 also altered the rank order of the ET antagonists tested. The results presented describe an in vivo system that accurately characterizes the ETA activity of ET antagonists.


Journal of Cardiovascular Pharmacology | 1995

Sarafotoxin S6c elicits a non-ETA or non-ETB-mediated pressor response in the pithed rat

Declan A. Flynn; Carol A. Sargent; Roman Brazdil; Thomas J. Brown; Alan Geoffrey Roach

Summary: Sarafotoxin S6c (Sx6c) is reported to evoke depressor and pressor effects via activation of endothelin (ET) ETB receptors located on the endothelium and smooth muscle, respectively. We have examined the effects of the selective ETB receptor antagonist BQ 788 on the fall and rise in diastolic blood pressure induced by Sx6c (1 nmol/kg, i.v.) in pithed rats. A dose-dependent reduction in both depressor and pressor response was observed. BQ 788 completely ablated the Sx6c-mediated fall in blood pressure at 1 mg/kg. In contrast, the pressor response was not completely abolished by 10 mg/kg BQ 788 (10 mg/kg: 16.5 < 3.0 mm Hg vs. control 49.0 ± 2.5 mm Hg). Co-administration of the ETA receptor antagonist BQ 123 (1.5 mg/kg) with BQ 788 produced no further antagonism of the Sx6c-mediated pressor response. BQ 788 plus BQ 123 (1.5 mg/kg) totally blocked the pressor response to ET-1 (0.1 nmol/kg, i.v.) suggesting a difference in the mechanism of action between the two agonists. In conclusion, a portion of the Sx6c-induced pressor response is resistant to blockade by known ETA and ETB receptor antagonists. Whether Sx6c acts on a novel ET receptor or produces a nonspecific effect remains to be determined.


European Journal of Medicinal Chemistry | 1997

Selective endothelin A receptor antagonists. 2. Discovery and structure-activity relationships of 5-ketopentanoic acid derivatives

Peter Charles Astles; Thomas J. Brown; Neil Victor Harris; M. F. Harper; Clive Mccarthy; Barry Porter; Christopher Smith; Roger John Aitchison Walsh

Summary The second in this series of papers describes the further progress made in the discovery of a potent and selective endothelin ETA receptor antagonist for the potential treatment of diseases in which endothelin has been shown to have a pathophysiological role including hypertension, ischaemic diseases and atherosclerosis. We describe herein the synthesis and structure-activity relationships of a novel series of 5-ketopentanoic acid derivatives exemplified by the lead compound 1 (IC50 0.72 μM, rat aortic ETAR). Optimisation of the in vitro binding of 1 led to the identification of a more potent compound (37) which exhibited an IC50 300-fold selectivity for the ETA receptor over the ETB receptor. This compound demonstrated functional antagonism of endothelin-induced vasoconstriction in vitro.


Journal of Medicinal Chemistry | 2000

Selective ET(A) antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives.

Peter Charles Astles; Thomas J. Brown; Frank Halley; Caroline M. Handscombe; Neil Victor Harris; Tahir N. Majid; Clive Mccarthy; Iain M. McLay; Andrew David Morley; Barry Porter; Alan Geoffrey Roach; Carol Sargent; Christopher Smith; Roger John Aitchison Walsh


Journal of Medicinal Chemistry | 1992

Synthesis and biological activity of trans(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide (RP 49356) and analogues: a new class of potassium channel opener.

Thomas J. Brown; Chapman Rf; Cook Dc; Hart Tw; McLay Im; Jordan R; Jonathan Stephen Mason; Malcolm Norman Palfreyman; Roger John Aitchison Walsh; Withnall Mt


Journal of Medicinal Chemistry | 1996

New low-density lipoprotein receptor upregulators acting via a novel mechanism.

Michael J. Ashton; Thomas J. Brown; Garry Fenton; Frank Halley; M. F. Harper; Peter M. Lockey; Barry Porter; Alan Geoffrey Roach; Keith Alfred James Stuttle; Nigel Vicker; Roger John Aitchison Walsh


The Journal of Clinical Endocrinology and Metabolism | 1997

In Vitro Expression of Endothelin-1 (ET-1) and the ETA and ETB ET Receptors by the Prostatic Epithelium and Stroma

Ewan S. Grant; Thomas J. Brown; Alan Geoffrey Roach; Brent C. Williams; Fouad K. Habib

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