Discovery of orally available 8-aza-5-thiaProstaglandin E1 analogs as highly selective EP4 agonists |
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Authors: | Kambe Tohru Maruyama Toru Nakano Masayuki Yamaura Yoshiyuki Shono Tomoyuki Seki Akiteru Sakata Kiyoto Maruyama Takayuki Nakai Hisao Toda Masaaki |
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Institution: | Minase Research Institute, Ono Pharmaceutical Co., Ltd., Mishima, Osaka 618–8585, Japan. kanbe@ono.co.jp |
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Abstract: | Analogs 8-aza-16-aryl prostaglandin E(1) (PGE(1)) and 8-aza-5-thia-16-arylPGE(1) were synthesized and evaluated with respect to their subtype receptor affinity and EP4 agonist activity for the purposes of identifying subtype-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. |
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