Discovery of orally available 8-aza-5-thiaProstaglandin E1 analogs as highly selective EP4 agonists.
作者： Tohru Kambe , Toru Maruyama , Masayuki Nakano , Yoshiyuki Yamaura , Tomoyuki Shono
DOI: 10.1248/CPB.59.1523
关键词: Chemistry 、 Prostaglandin E1 、 Pharmacology 、 In vivo 、 Prostaglandin 、 Receptor 、 Agonist 、 Tumor necrosis factor alpha 、 Pharmacokinetics 、 EP4 Receptor
摘要: Analogs 8-aza-16-aryl prostaglandin E1 (PGE1) and 8-aza-5-thia-16-arylPGE1 were synthesized evaluated with respect to their subtype receptor affinity EP4 agonist activity for the purposes of identifying subtype-selective agonists that demonstrate oral efficacy. Using an inhibition assay lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in rats, representative compounds pharmacokinetic profiles vivo Structure–activity relationships (SARs) characterized presented. Of tested, several demonstrated better exposure and/or efficacy compared previously reported analog 2a.
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