Synthesis, Modeling, and Biological Properties of Fluoroprostacyclin Analogues: Potent Agonists for Prostanoid Receptors.

Prostacyclin (PGI2, epoprostenol) and its more stable analogues iloprost and cicaprost are used in the treatment of pulmonary arterial hypertension (PAH) and other related diseases. Currently, PGI2 therapy is the most effective treatment for PAH, but is administered intravenously due to its instability under physiological conditions. We considered creating more chemically stable hybrids of PGI2 by merging essential features of iloprost/cicaprost with a more stable C-7 fluorinated PGI2, which maintained the cyclic enol ether. The synthesis employed our key bicyclic enal and furnished the required PGI2 analogues in just 7-8 steps, providing the most expedient route to this class of molecules. This led to the discovery of compound 9, a picomolar-potent, IP receptor-selective, and chemically stable PGI2 analogue that combined the ω-side chain of cicaprost with the C-7 difluorinated enol ether of PGI2. This compound provides the most potent PGI2 analogue tested to date.