title: Discovery of orally available 8-aza-5-thiaProstaglandin E1 analogs as highly selective EP4 agonists.
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.
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., Mishima, Osaka 618–8585, Japan. kanbe@ono.co.jp
authors: Tohru
authors: T
authors: Kambe
authors: Toru
authors: T
authors: Maruyama
authors: Masayuki
authors: M
authors: Nakano
authors: Yoshiyuki
authors: Y
authors: Yamaura
authors: Tomoyuki
authors: T
authors: Shono
authors: Akiteru
authors: A
authors: Seki
authors: Kiyoto
authors: K
authors: Sakata
authors: Takayuki
authors: T
authors: Maruyama
authors: Hisao
authors: H
authors: Nakai
authors: Masaaki
authors: M
authors: Toda
mesh_terms: D000284:Administration, Oral; D000527:Alprostadil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D011459:Prostaglandins E, Synthetic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C028327:8-azaprostaglandin E1; D008070:Lipopolysaccharides; D011459:Prostaglandins E, Synthetic; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D000527:Alprostadil