The 15R and 15S epimers of a series of phenyl substituted analogs of 17-phenyl-18,19,20-trinorprostaglandin F2 alpha isopropyl ester [(15S)-3] have been synthesized. The intraocular pressure (IOP) lowering effects and potential side effects of these novel derivatives have been studied in cats and rabbits. In addition, the effects of selected analogues on IOP have been studied in monkeys. Furthermore, we have hydrolyzed some of the isopropyl esters and assessed the ability of the resulting carboxylic acids to contract the cat iris sphincter muscle in vitro. In general, the 15S-derivatives were more active than the 15R-epimers. Derivatives substituted with an acetyl group in the benzene ring appeared to have a better side effect profile as compared to (15S)-3. Furthermore, substitution with an aromatic moiety had a dramatic effect on the activity in that the resulting compounds reduced IOP in cats but had little effect on the pupil diameter. Thus, the activity profile of (15S)-3 may be changed by the introduction of substituents in the benzene ring.