Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension

• Published in: Journal of medicinal chemistry Vol. 58; no. 18; pp. 7128 - 7137
• Main Authors: Asaki, Tetsuo, Kuwano, Keiichi, Morrison, Keith, Gatfield, John, Hamamoto, Taisuke, Clozel, Martine
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 24.09.2015
• Subjects: Acetamides - chemistry; Acetamides - pharmacology; Acetamides - therapeutic use; Acetates - chemistry; Acetates - pharmacology; Acetates - therapeutic use; Administration, Oral; Animals; CHO Cells; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cricetulus; Dogs; Double-Blind Method; Haplorhini; Humans; Hypertension, Pulmonary - drug therapy; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - physiology; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Pulmonary Artery - cytology; Pyrazines - chemistry; Pyrazines - pharmacology; Pyrazines - therapeutic use; Randomized Controlled Trials as Topic; Rats; Receptors, Epoprostenol - agonists; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00698

Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an N-acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial.