Structure-activity studies of configurationally rigid arylprostaglandins

Potent, albeit nonselective, smooth-muscle stimulant activity has been previously reported for 16-phenoxy- and 17-phenylprostaglandins, a finding that led to the design and development of the tissue-selective uterine stimulant sulprostone. As an extension of this work, analogues incorporating the 16-phenoxy and 17-phenyl substituents into the rigid indanyl, tetrahydronaphthyl, dihydrobenzofuryl, and dihydrobenzopyranyl ring systems were prepared and evaluated for uterine stimulant activity in vitro and diarrheal effects in vivo. Since these cyclic groups, with the exception of the indanyl, contain a chiral center, both optical antipodes were prepared. These studies demonstrate that ring size, heteroatom, and absolute configuration at C-16 are important determinants for potency and selectivity.