Prostaglandin FP receptor antagonists: discovery pharmacological characterization and therapeutic utility

摘要

In contrast to the availability of potent and selective antagonists of several prostaglandin receptor types (including DP , DP , 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 PGF , but these have failed to gain prominence. The fluorinated PGF 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 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.