Discovery of an 8-aza-5-thiaProstaglandin E1 analog as a highly selective EP4 receptor agonist |
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Authors: | Kambe Tohru Maruyama Toru Naganawa Atsushi Asada Masaki Seki Akiteru 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: | For the purpose of discovering an orally available EP4 subtype-selective agonist, a series of 8-aza prostaglandin E(1) (PGE(1)) analogs were synthesized and evaluated for their affinity for PGE(2) receptor subtypes. Additionally, the structure-activity relationships of these compounds were studied. Among the tested compounds, the 8-aza PGE(1) analog 6 and 8-aza-5-thiaPGE(1) analog 12 had highly potent EP4 receptor affinity, good functional activity, and excellent subtype-selectivity. Furthermore, these analogs demonstrated good stability in human liver microsomes. As a result, we concluded that these two series of 8-aza PGE(1) analogs could be promising chemical leads for an orally available EP4 subtype-selective agonist. |
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