Prostanoid receptor antagonists: development strategies and therapeutic applications

R.L. Jones, M.A. Giembycz, D.F. Woodward

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are 'non-prostanoid' (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage.
LanguageEnglish
Pages104-145
Number of pages41
JournalBritish Journal of Pharmacology
Volume158
Issue number1
DOIs
Publication statusPublished - Sep 2009

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Receptors, Prostaglandin E, EP1 Subtype
Cyclooxygenase Inhibitors
Prostaglandin-Endoperoxide Synthases
Prostaglandins
Prostaglandin E Receptors
Prostaglandin D2
Thromboxanes
Sulfonamides
Epoprostenol
Aspirin
Libraries
Pharmacology
Safety
Therapeutics
Pharmaceutical Preparations

Keywords

  • prostaglandin
  • thromboxane A(2)
  • prostacyclin
  • prostamide
  • prostanoid receptor antagonist
  • development strategy
  • high-throughput screening
  • acyl-sulphonamide
  • pA(2) values
  • therapeutic applications

Cite this

Jones, R.L. ; Giembycz, M.A. ; Woodward, D.F. / Prostanoid receptor antagonists: development strategies and therapeutic applications. In: British Journal of Pharmacology. 2009 ; Vol. 158, No. 1. pp. 104-145.
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Prostanoid receptor antagonists: development strategies and therapeutic applications. / Jones, R.L.; Giembycz, M.A.; Woodward, D.F.

In: British Journal of Pharmacology, Vol. 158, No. 1, 09.2009, p. 104-145.

Research output: Contribution to journalArticle

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