Jiang Guang-Liang, Nieves Amelia, Im Wha Bin, Old David W, Dinh Danny T, Wheeler Larry
Department of Biological Sciences, Herbert Research Center, Allergan, Inc., 2525 Dupont Dr., R&D3-2B, Irvine, CA 92612, USA.
J Pharmacol Exp Ther. 2007 Jan;320(1):22-8. doi: 10.1124/jpet.106.111146. Epub 2006 Sep 28.
Inflammatory bowel disease (IBD) is often triggered and/or exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs). Among various prostanoids affected by NSAIDs, prostaglandin E2 (PGE2), in particular, seems to play critical roles in IBD via the EP4 receptor, one of the four PGE2 receptor subtypes (EP1-4). An EP4 agonist, [[3-[[(1R,2S,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl]-5-oxocyclopentyl]thio]propyl]thio]-acetic acid, C22H30O6S2 (ONO-AE1-329), for example, when topically applied, has been reported to ameliorate typical colitis symptoms by suppressing the production of cytotoxic cytokines in the dextran sodium sulfate (DSS)-induced colitis model. EP4 agonists are also known, however, for their ability to protect epithelial cells from apoptosis in vitro, which may contribute to the protection of mucosal barrier functions. To investigate this potential application, we have tested another EP4-selective agonist in the DSS-indomethacin mouse colitis model. 7-[2-(3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester, C23H33NO4 (AGN205203), an analog from the 8-azapiperidinone series of EP4 agonists, is metabolically and chemically more stable than the ONO agonist, because of its lack of oxidizable sulfur atoms in the alpha-chain and of 11-OH group, a potential source of beta-elimination reaction. Treatment of mice subcutaneously with AGN205203 at 3 mg/kg/day minimized colitis symptoms, such as weight loss, diarrhea, and colonic bleeding. Further histological examination of colons revealed healthy surface columnar epithelial cells free of erosion and ulceration compared with those without the drug treatment. At cellular level, the drug treatment decreased colon epithelial apoptosis, prevented goblet cell depletion, and promoted epithelial regeneration. AGN205203 may be unique among known EP4 agonists for its metabolic and chemical stability, and it is amenable to systemic applications for the prevention and recovery of IBD.
炎症性肠病（IBD）常由非甾体抗炎药（NSAIDs）引发和/或加重。在受NSAIDs影响的各种前列腺素中，前列腺素E2（PGE2）似乎尤其通过EP4受体在IBD中发挥关键作用，EP4受体是四种PGE2受体亚型（EP1 - 4）之一。例如，一种EP4激动剂，[[3 - [[(1R,2S,3R)-3 - 羟基 - 2 - [(1E,3S)-3 - 羟基 - 4 - [3 - (甲氧基甲基)苯基] - 1 - 丁烯基] - 5 - 氧代环戊基]硫代]丙基]硫代] - 乙酸，C22H30O6S2（ONO - AE1 - 329），据报道，局部应用时，可通过抑制葡聚糖硫酸钠（DSS）诱导的结肠炎模型中细胞毒性细胞因子的产生来改善典型的结肠炎症状。然而，EP4激动剂还因其在体外保护上皮细胞免于凋亡的能力而闻名，这可能有助于保护黏膜屏障功能。为了研究这种潜在应用，我们在DSS - 吲哚美辛小鼠结肠炎模型中测试了另一种EP4选择性激动剂。7 - [2 - (3 - 羟基 - 4 - 苯基 - 丁 - 1 - 烯基) - 6 - 氧代 - 哌啶 - 1 - 基] - 庚酸甲酯，C23H33NO4（AGN205203），一种来自8 - 氮杂哌啶酮系列的EP4激动剂类似物，由于其α链中缺乏可氧化的硫原子以及11 - OH基团（β消除反应的潜在来源），在代谢和化学性质上比ONO激动剂更稳定。以3 mg/kg/天的剂量皮下注射AGN205203治疗小鼠，可使结肠炎症状（如体重减轻、腹泻和结肠出血）降至最低。对结肠进行进一步的组织学检查发现，与未接受药物治疗的小鼠相比，其表面柱状上皮细胞健康，无糜烂和溃疡。在细胞水平上，药物治疗减少了结肠上皮细胞凋亡，防止了杯状细胞耗竭，并促进了上皮再生。AGN205203在已知的EP4激动剂中可能因其代谢和化学稳定性而独具特色，并且适合用于IBD的预防和恢复的全身应用。
