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.