Discovery of orally available 8-aza-5-thiaProstaglandin E 1 analogs as highly selective EP4 agonists

Abstract

Analogs 8-aza-16-aryl prostaglandin E 1 (PGE 1) and 8-aza-5-thia-16-arylPGE1 were synthesized and evaluated with respect to their subtype receptor affinity and EP4 agonist activity for the purposes of identifying sub-type- selective EP4 agonists that demonstrate oral efficacy. Using an inhibition assay of lipopolysaccharide (LPS)- induced tumor necrosis factor (TNF)-α production in rats, representative compounds were evaluated for their pharmacokinetic profiles and in vivo efficacy. Structure-activity relationships (SARs) were characterized and presented. Of the compounds tested, several demonstrated better oral exposure and/or in vivo efficacy compared with the previously reported analog 2a. © 2011 Pharmaceutical Society of Japan.