Discovery of orally available 8-aza-5-thiaProstaglandin E1 analogs as highly selective EP4 agonists.

نویسندگان

  • Tohru Kambe
  • Toru Maruyama
  • Masayuki Nakano
  • Yoshiyuki Yamaura
  • Tomoyuki Shono
  • Akiteru Seki
  • Kiyoto Sakata
  • Takayuki Maruyama
  • Hisao Nakai
  • Masaaki Toda
چکیده

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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عنوان ژورنال:
  • Chemical & pharmaceutical bulletin

دوره 59 12  شماره 

صفحات  -

تاریخ انتشار 2011