Prostaglandin FP receptor antagonists: discovery, pharmacological characterization and therapeutic utility.

Abstract

In contrast to the availability of potent and selective antagonists of several prostaglandin receptor types (including DP1 , DP2 , EP and TP receptors), there has been a paucity of well-characterized, selective FP receptor antagonists. The earliest ones included dimethyl amide and dimethyl amine derivatives of PGF2α , but these have failed to gain prominence. The fluorinated PGF2α analogues, AL-8810 and AL-3138, were subsequently discovered as competitive and non-competitive FP receptor antagonists respectively. Non-prostanoid structures, such as the thiazolidinone AS604872, the D-amino acid-based oligopeptide PDC31 and its peptidomimic analogue PDC113.824 came next, but the latter two are allosteric inhibitors of FP receptor signalling. AL-8810 has a sub-micromolar in vitro potency and ≥2 log unit selectivity against most other PG receptors when tested in several cell- and tissue-based functional assays. Additionally, AL-8810 has demonstrated therapeutic efficacy as an FP receptor antagonist in animal models of stroke, traumatic brain injury, multiple sclerosis, allodynia and endometriosis. Consequently, it appears that AL-8810 has become the FP receptor antagonist of choice. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.

• Authors: Najam A Sharif, Peter G Klimko
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 176 Issue 8 Pg. 1059-1078 (04 2019) ISSN: 1476-5381 [Electronic] England
• PMID: 29679483 (Publication Type: Journal Article, Review)
• Copyright: © 2018 The British Pharmacological Society.

Chemical References

• Prostaglandins F, Synthetic
• Receptors, Prostaglandin
• prostaglandin F2alpha receptor
• Dinoprost

Topics

• Animals
• Dinoprost (analogs & derivatives, pharmacology)
• Drug Discovery (methods, trends)
• Humans
• Prostaglandins F, Synthetic (chemistry, pharmacology)
• Receptors, Prostaglandin (agonists, antagonists & inhibitors, metabolism)