Potent, Selective, Water Soluble, Brain-Permeable EP2 Receptor Antagonist for Use in Central Nervous System Disease Models

Abstract

Activation of prostanoid EP2 receptor exacerbates neuroinflammatory and neurodegenerative pathology in central nervous system diseases such as epilepsy, Alzheimer’s disease, and cerebral aneurysms. A selective and brain-permeable EP2 antagonist will be useful to attenuate the inflammatory consequences of EP2 activation and to reduce the severity of these chronic diseases. We recently developed a brain-permeable EP2 antagonist 1 (TG6-10-1), which displayed anti-inflammatory and neuroprotective actions in rodent models of status epilepticus. However, this compound exhibited moderate selectivity to EP2, a short plasma half-life in rodents (1.7 h) and low aqueous solubility (27 μM), limiting its use in animal models of chronic disease. With lead-optimization studies, we have developed several novel EP2 antagonists with improved water solubility, brain penetration, high EP2 potency, and selectivity. These novel inhibitors suppress inflammatory gene expression induced by EP2 receptor activation in a microglial cell line, reinforcing the use of EP2 antagonists as anti-inflammatory agents.

Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease

“…On days 1–6 after dosing began, we found an average 17-fold higher concentration of TG11-77 free base in plasma, than its EP2 potency (Schild K B = 9.7 nM) of the free base (Fig. 9 A) [ 49 ]. In the same cohort of mice ( n = 4), on day 7 the concentration of TG11-77 in the plasma varied between 4.2 and 46.5-fold higher than its potency and it was 15–16-fold higher in the brain than its potency.…”

“…Dotted line represents the potency (Schild K B ) of TG11-77.HCl = 9.7 nM. D EP2 Selectivity was determined by measuring the potency of TG11-77.HCl for other prostanoid receptors (EP4, DP1 and IP) by a cAMP mediated TR-FRET assay using human EP2 expressed C6-gloma cells as shown before [ 49 ] …”

“…Moreover, a selective PGE 2 receptor EP2 antagonist also enhances Aβ-phagocytosis in vitro in a macrophage cell line [ 47 ]. Furthermore, our recent in vitro study revealed that in an activated state, a murine microglial cell line stably transfected with human EP2 receptors (BV2-hEP2), when challenged with a specific EP2 receptor agonist, produced inflammation that was competitively inhibited by a selective EP2 antagonist [ 48 , 49 ]. With these rationales, here we investigated whether a selective and potent EP2 antagonist, ameliorates neuroinflammation in 5xFAD model in the presence (two-hit), and absence (single-hit—genetic) of a second peripheral inflammatory insult by LPS.…”

Endometriosis: Etiology, pathobiology, and therapeutic prospects

“…An alternative approach has been to test agonists or antagonists for one or more of the prostaglandin receptors (EP1-EP4). Studies in mouse models have provided promising results including a reduction in evoked pain responses (Arosh et al, 2015;Greaves et al, 2017) (Table 4); future trials are likely to benefit from development of a new generation of highly specific brain-permeable drugs (Amaradhi et al, 2020). Other examples of agents that appeared promising in mouse models and that may be acting by suppressing or modifying inflammatory processes include novel estrogen receptor ligands (Zhao et al, 2015) and the anti-helminth drug, niclosamide (Prather et al, 2016) (Table 4).…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–7

“…This work describes the improvement of selectivity and drug-like properties of the brain-permeating lead TG6-10-1. The optimized antagonist, 2-[(4,6-dimethylpyridin-2-yl)amino]- N -[2-(2-methyl-1 H -indol-3-yl)ethyl]pyrimidine-5-carboxamide hydrochloride (TG11-77·HCl), has a higher selectivity index, suitable brain permeability and excellent water solubility [ 54 ].…”