Selexipag was approved by the United States FDA on December 22, 2015 for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce risk of hospitalization. PAH is a relatively rare disease with usually a poor prognosis requiring more treatment options to prolong long-term outcomes. Marketed by Actelion Pharmaceuticals under brand name Uptravi, selexipag and its active metabolite, ACT-333679 (MRE-269), act as agonists of the prostacyclin receptor to increase vasodilation in the pulmonary circulation and decrease elevated pressure in the blood vessels supplying blood to the lungs. Selexipag is a selective prostacyclin (IP, also called PGI2) receptor agonist. The key features of pulmonary arterial hypertension include a decrease in prostacyclin and prostacyclin synthase (enzyme that helps produce prostacyclin) in the lung. Prostacyclin is a potent vasodilator with anti-proliferative, anti-inflammatory, and anti-thrombotic effects; therefore, there is strong rationale for treatment with IP receptor agonists. Selexipag is chemically distinct as it is not PGI2 or a PGI2 analogue and has high selectivity for the IP receptor. It is metabolized by carboxylesterase 1 to yield an active metabolite (ACT-333679) that is approximately 37 times more potent than selexipag. Both selexipag and its metabolite are selective for the IP receptor over other prostanoid receptors. Selexipag is marketed under the brand name UPTRAVI, indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.

Iloprost is a second generation structural analog of prostacyclin (PGI) with about ten-fold greater potency than the first generation stable analogs, such as carbaprostacyclin. Iloprost binds with equal affinity to human prostacyclin (Prostanoid IP) and prostaglandin EP1 receptors. Iloprost constricts the ilium and fundus circular smooth muscle as strongly as prostaglandin E2 (PGE2) itself. Iloprost inhibits the ADP, thrombin, and collagen-induced aggregation of human platelets. In whole animals, iloprost acts as a vasodilator, hypotensive, antidiuretic, and prolongs bleeding time. All of these properties help to antagonize the pathological changes that take place in the small pulmonary arteries of patients with pulmonary hypertension. Used for the treatment of pulmonary arterial hypertension.

Treprostinil (marketed under the trade names Remodulin for infusion) is a vasodilator that is used for the treatment of pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH) is a disease in which blood pressure is abnormally high in the arteries between the heart and lungs. PAH is characterized by symptoms of shortness of breath during physical exertion. The condition can ultimately lead to heart failure. Treprostinil is a potent oral antiplatelet agent. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. Other studies have shown that treprostinil causes a dose-related negative inotropic and lusitropic effect. No major effects on cardiac conduction have been observed. Treprostinil had high affinity for the Prostaglandin D2 receptor (DP1), Prostaglandin E2 receptor EP2 subtype (EP2) and Prostaglandin D2 receptor (IP) receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, Prostaglandin F (FP) and thromboxane (TP) receptors. Treprostinil has demonstrated a unique effect on PPAR gamma, a transcription factor important in vascular pathogenesis as a mediator of proliferation, inflammation and apoptosis. Through a complementary, yet cyclic AMP-independent pathway, treprostinil activates PPARs, another mechanism that contributes to the anti-growth benefits of the prostacyclin class.

Epoprostenol (marketed as FLOLAN, VELETRI) is a prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. Epoprostenol (PGI2, PGX, prostacyclin), a metabolite of arachidonic acid, is a naturally occurring prostaglandin with potent vasodilatory activity and inhibitory activity of platelet aggregation. FLOLAN (epoprostenol sodium) for Injection is a sterile sodium salt formulated for intravenous (IV) administration. Epoprostenol has two major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated brudycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. FLOLAN is indicated for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy.

Pimilprost (SM-10902) and its free acid, SM-10906 are new stable 3-oxa-methano prostaglandin (PG) I1 analogs, SM-10902 is a prodrug of SM-10906. SM-10906, but not SM-10902 was demonstrated to be an agonist for IP receptors. SM-10906 was shown to exert its anti-platelet and vasodilatory activities through the increase of the cAMP level. Pimilprost was being developed by Dainippon Sumitomo Pharma (formerly Sumitomo Pharmaceuticals) in Japan for the treatment of skin ulcers. In Japan, an NDA was filed for pimilprost and was awaiting registration. However, development appears to have been discontinued.

Cicaprost is a prostacyclin receptor (IP) agonist and orally active prostacyclin analog with potent systemic and pulmonary vasodilatation and anti-inflammatory activity. In preclinical models, Cicaprost treatment largely prevented the hypercholesterolemia-related impairment of coronary vasodilation and nitric oxide release in Isolated Langendorff-hearts. Cicaprost inhibits proinflammatory chemokines production not only from lipopolysaccharides (LPS) or (tumor necrosis factor-alpha) induced primary human monocyte-derived macrophages but also from LPS-stimulated monocyte-derived dendritic cells. Besides that Cicapost strongly inhibits lymph node and organ metastases of spontaneously metastasizing mammary tumors with a mode of action different from cytostatic or antihormonal drugs. In animal models, Cicaprost prevents metastasis if given continuously from the day of tumor implantation, and is effective in reducing metastasis if treatment is begun following surgical removal of the primary tumor when micrometastases are already present. Clinical trials of Cicaprost in healthy male volunteers demonstrate significant anti-platelet and vasodilatory effects.

Ciprostene is a synthetic, chemically stable analog of prostacyclin (PGI2). In animal models, administration of ciprostene resulted in dose-dependent hypotension, tachycardia, and inhibition of ex vivo ADP-induced platelet aggregation. Ciprostene was evaluated in clinical trials in patients with peripheral vascular disease. It was found to reduce restenosis in patients with coronary artery disease undergoing therapeutic percutaneous transluminal coronary angioplasty.

15-Epi-prostaglandin E2 (15R-Prostaglandin E2) is the C-15 epimer of the naturally occurring 15S-Prostaglandin E2 (15S-PGE2) isomer. 15-Epi-prostaglandin E2 is the most physiologically abundant eicosanoid, which is produced predominantly from arachidonic acid by COX and PGES, and exists at some level in nearly all cell types. Prostaglandin E2 acts on four different receptors termed EP1 through EP4 yielding an astounding array of biological effects, but this compound shows much lower potency in most biological assays; however acid catalyzed epimerization can convert this compound to the active form - 15S-Prostaglandin E2. In the in vivo assay, 15R-PGE2 showed anti-inflammatory activity, as well as in vitro inhibition of elastase release from polymorphonuclear cells. In the from polymorphonuclear cells degranulation assay, 15R-PGE2, was the most active compound in the inhibition of myeloperoxidase release.

Beraprost is a stable, orally active prostacyclin analogue. Beraprost acts by binding to prostacyclin membrane receptors ultimately inhibiting the release of Ca2+ from intracellular storage sites. This reduction in the influx of Ca2+ has been postulated to cause relaxation of the smooth muscle cells and vasodilation. Beraprost is indicated for the treatment of pulmonary hypertension and improvement of ulcers, pain & feeling of coldness associated with chronic arterial occlusion. In addition beraprost displays thyroid hormone receptor antagonistic properties.

Iloprost is a second generation structural analog of prostacyclin (PGI) with about ten-fold greater potency than the first generation stable analogs, such as carbaprostacyclin. Iloprost binds with equal affinity to human prostacyclin (Prostanoid IP) and prostaglandin EP1 receptors. Iloprost constricts the ilium and fundus circular smooth muscle as strongly as prostaglandin E2 (PGE2) itself. Iloprost inhibits the ADP, thrombin, and collagen-induced aggregation of human platelets. In whole animals, iloprost acts as a vasodilator, hypotensive, antidiuretic, and prolongs bleeding time. All of these properties help to antagonize the pathological changes that take place in the small pulmonary arteries of patients with pulmonary hypertension. Used for the treatment of pulmonary arterial hypertension.