Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
Eur J Med Chem. 2012 Apr;50:179-95. doi: 10.1016/j.ejmech.2012.01.053. Epub 2012 Feb 6.
Cyclooxygenase (COX) is a key rate-limiting enzyme for prostaglandin (PG) production cascades in the human body. The mechanisms of both the anti-inflammation effects and the side-effects of traditional COX inhibitors are associated with the existence of two COX isoforms. Thus while COX-1 is predominantly expressed ubiquitously and constitutively, and it serves a housekeeping role in processes such as gastrointestinal (GI) mucosa protection, COX-2 is absent or exhibits a low level of expression in most tissues, and is highly upregulated in response to endotoxin, virus, inflammatory or tissue-injury stimuli/signals, and tumour promoter in the various types of organs, tissues, and cells. Furthermore, COX-2 contribution to PGE(2) and PGI(2) production evokes and sustains systemic or peripheral inflammatory disease, but it is not involved in the COX-1-mediated GI tract events. Also, hypersensitivity of aspirin owing to its inhibitory action against COX-1 is a significant concern clinically. Consequently, highly selective COX-2 inhibitors have been needed for the treatment of inflammatory- and inflammation related-diseases that include pyrexia, inflammation, pain, rheumatoid arthritis, osteoarthritis, and cancers. In this study, a series of novel [2-{[(4-substituted or 4,5-disubstituted)-pyridin-2-yl]carbonyl}-(5- or 6-substituted or 5,6-disubstituted)-1H-indol-3-yl]acetic acid analogues was designed, synthesized, and evaluated to identify potent and selective COX-2 inhibitors as potential agents against inflammatory diseases. As significant findings, the present study clarified unique structure-activity relationship of the analogues toward potent and selective COX-2 inhibition in vitro, and identified 2-{6-fluoro-2-[4-methyl-2-pridinyl)carbonyl]-1H-indol-3-yl}acetic acid as a potent and selective COX-2 inhibitor in vitro that demonstrated orally potent anti-inflammation efficacy against carrageenan-induced oedema formation in the foot of SPF/VAF male SD rats as a peripheral inflammation model in vivo.
环氧化酶（COX）是人体内前列腺素（PG）产生级联反应的关键限速酶。传统 COX 抑制剂的抗炎作用和副作用机制都与两种 COX 同工酶的存在有关。因此，COX-1 主要在普遍和持续存在的情况下表达，并在胃肠道（GI）黏膜保护等过程中发挥管家作用，而 COX-2 在大多数组织中不存在或表达水平较低，但在各种类型的器官、组织和细胞中，对内毒素、病毒、炎症或组织损伤刺激/信号以及肿瘤促进剂高度上调。此外，COX-2 对 PGE（2）和 PGI（2）产生的贡献引发并维持全身或外周炎症性疾病，但它不参与 COX-1 介导的胃肠道事件。此外，由于其对 COX-1 的抑制作用，阿司匹林的过敏反应是临床上一个重要的关注点。因此，需要高度选择性的 COX-2 抑制剂来治疗包括发热、炎症、疼痛、类风湿关节炎、骨关节炎和癌症在内的炎症和炎症相关疾病。在这项研究中，设计、合成并评估了一系列新型[2-（[（4-取代或 4,5-二取代）-吡啶-2-基]羰基）-（5-或 6-取代或 5,6-二取代）-1H-吲哚-3-基]乙酸类似物，以鉴定出强效和选择性 COX-2 抑制剂作为对抗炎症性疾病的潜在药物。作为重要的发现，本研究阐明了类似物对体外强效和选择性 COX-2 抑制的独特构效关系，并确定 2-{6-氟-2-[4-甲基-2-吡啶基]羰基}-1H-吲哚-3-基}乙酸作为一种在体外具有强效和选择性 COX-2 抑制作用的抑制剂，在 SPF/VAF 雄性 SD 大鼠的足爪中，作为体内外周炎症模型，对角叉菜胶诱导的水肿形成具有口服有效的抗炎作用。
