Three major mechanisms are proposed to underlie migraine attacks: vascular (due to cerebral vasodilation), neurological (due to abnormal firing) and neurogenic dural inflammation (due to the release of inflammatory neuropeptides). Prostaglandins are naturally existing molecules that mediate inflammatory and vascular reactions. In the last decade, evidence has accumulated that prostaglandin E2 (PGE2) binding with receptor EP4 (one of the four receptors PGE2 is known to bind) causes dilation of small cerebral vessels, while not affecting coronary and pulmonary arteries.
AP-1531, is a first-in-class, orally available, potent and selective EP4 receptor antagonist. COX inhibitors inhibit enzymes in the prostanoid biosynthesis pathway, with broad impacts on a number of prostaglandins resulting in serious side effects. In contrast, AP-1531 specifically antagonizes PGE2-EP4 signaling. We believe this highly specific interaction reduces the likelihood of side effects. AP-1531 has been shown in the rat closed-cranial window model of migraine to inhibit prostaglandin-induced vasodilation of cranial blood vessels resulting in a robust reduction in inflammation and migraine pain.
Since EP4 receptors are discretely localized, the overall safety profile of EP4 receptor antagonists may be superior to triptans and NSAIDs. The safety, tolerability, pharmacokinetics and pharmacodynamics of AP-1531 have been evaluated in six Phase I clinical trials in healthy volunteers; AP-1531 was found to be well tolerated at doses that provided statistically significant analgesic effects. Because progression of rheumatoid arthritis also involves PGE2-EP4 signaling, Ariel potentially may evaluate AP-1531 for this indication. In various preclinical models, AP-1531 was shown to effectively decrease composite pain scores, reduce inflammation and inhibit adjuvant-induced arthritis.
AP-1531 selectively binds with the EP4 receptors to directly inhibit cerebrovascular dilation to provide direct anti-hyperanalgesic activity.