Development of a highly selective EP2-receptor agonist. Part 2: identification of 16-Hydroxy-17,17-trimethylene 9β-chloro PGF derivatives

Abstract

Further chemical modification of 1a and 2 was undertaken to identify a more chemically stable selective EP2-receptor agonist for development as a clinical candidate. 9beta-chloro PG analogues 4a-e and 5a, c-e were found to be potent and selective EP2-receptor agonists. Among them, the compound 4aLy, which is a chemically stabilized lysine salt of 4a, exhibited an excellent profile both in biological activities and physicochemical properties. The agonist 4aLy was found to suppress uterine motility in anesthetized pregnant rats, while PGE2 stimulated uterine motility. Structure-activity relationships (SARs) are discussed.

Neuroprotective Function of the PGE2EP2 Receptor in Cerebral Ischemia

“…In dispersed hippocampal cultures, activation of the EP2 receptor (10 nM butaprost) significantly protected neurons from glutamate-mediated toxicity (Fig. 4C) (EC 50 of butaprost is 23 nM) (Tani, 2002). These results were confirmed in hippocampal organotypic cultures, in which EP2 receptor activation by butaprost in nanomolar concentrations also significantly protected hippocampal pyramidal neurons after NMDA and OGD (Fig.…”

Prostanoid Receptor EP2 as a Therapeutic Target

“…54-56 Studies also indicate that EP2 plays protective and deleterious roles in the peripheral disease models. EP2 activation by a selective agonist ONO-AE1-259-01 57 ( 5) (Figure 4) in a rat model of retinal degeneration, increases the retinal arteriolar diameter and fundus blood flow and also prevents NMDA induced exitotoxic injuries to rat retina, suggesting that EP2 plays a role in the regulation of ocular hemodynamics. 58, 59 An EP2 agonist CP-533536 60 ( 7) (Figure 4) has been shown to accelerate bone-healing in a preclinical canine model of bone fracture.…”

“…In a potency assay, 3 showed nearly the same activity for EP2 and IP receptors with an EC 50 of 32 nM and 25 nM, respectively (Table 1). 75 The other agonist in the same class represented as compound 4 57 (Figure 4) appears very selective for the EP2 receptor over other prostanoid receptors. The affinity of 4 to EP2 is nearly 10-fold higher than that of 1 and 20-fold higher than that of 3 (Table 1).…”

“…However, in functional assays, it has nearly the same potency as 1 , and roughly a 10-fold higher potency than 3 . 57 Compound 4 is found to be unstable as the free acid, but its stability is markedly improved when it is converted to the lysine salt. 57 Compound 5 shows a higher binding affinity for EP2 ( K i = 1.7 nM), a 22-fold higher affinity than 1 and 42-fold higher affinity than 3 .…”

“…57 Compound 4 is found to be unstable as the free acid, but its stability is markedly improved when it is converted to the lysine salt. 57 Compound 5 shows a higher binding affinity for EP2 ( K i = 1.7 nM), a 22-fold higher affinity than 1 and 42-fold higher affinity than 3 . Compound 5 also shows ~700 to 1500-fold selectivity for EP2 over other prostanoid receptors such as EP1, EP3, EP4 and IP.…”