title: Discovery of an 8-aza-5-thiaProstaglandin E1 analog as a highly selective EP4 receptor agonist.
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.
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: Atsushi
authors: A
authors: Naganawa
authors: Masaki
authors: M
authors: Asada
authors: Akiteru
authors: A
authors: Seki
authors: Takayuki
authors: T
authors: Maruyama
authors: Hisao
authors: H
authors: Nakai
authors: Masaaki
authors: M
authors: Toda
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011459:Prostaglandins E, Synthetic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000378:metabolism
chemical_list: C028327:8-azaprostaglandin E1; D011459:Prostaglandins E, Synthetic; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000527:Alprostadil