Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.
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.
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd. , 14 Nishinosho-Monguchi-Cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.
Tetsuo
T
Asaki
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd. , 14 Nishinosho-Monguchi-Cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.
Keiichi
K
Kuwano
Drug Discovery Department, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, Allschwil CH4123, Switzerland.
Keith
K
Morrison
Drug Discovery Department, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, Allschwil CH4123, Switzerland.
John
J
Gatfield
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd. , 14 Nishinosho-Monguchi-Cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.
Taisuke
T
Hamamoto
Drug Discovery Department, Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16, Allschwil CH4123, Switzerland.
Martine
M
Clozel
D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000085:Acetates / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003412:Cricetulus; D004285:Dogs; D004311:Double-Blind Method; D000882:Haplorhini; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000166:cytology; D011719:Pyrazines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D044006:Receptors, Epoprostenol / Q000819:agonists*; D013329:Structure-Activity Relationship
D000081:Acetamides; D000085:Acetates; D010975:Platelet Aggregation Inhibitors; D011719:Pyrazines; D044006:Receptors, Epoprostenol; C523468:selexipag; C531934:(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid