Synthesis and properties of novel fluoroprostacyclins - Potent and stable prostacyclin agonists

Synthesis and structure-activity relationship of novel fluoroprostacyclin derivatives stabilized by one or two fluorine atoms adjacent to the acid labile enol ether has been studied. A variety of alpha-chain modified 7-fluoroprostacyclin derivatives bearing cycloalkylene groups were synthesized by three-component coupling approach or utilization of methylenecyclopentanone (the Stork's intermediate) and pharmacologically evaluated. 7-Fluoro-2,4-methylene-17,20-dimethylprostacyclin (1) exerted potent and longlasting anti-anginal activity in vivo in oral administration. Novel 7,7-difluoroprostacyclin derivatives were also synthesized and found to be more stable analogs with very potent inhibitory activities for platelet aggregation. 7,7-Difluoro-18,19-didehydro-16,20-dimethylprostacyclin (AFP-07, 2) was shown to be a highly selective and potent agonist for prostacyclin receptor.