Woodward David F, Wang Jenny W, Spada Clayton S, Carling Robert W, Martos Jose L, Pettit Simon, Kangasmetsa Jussi, Waterbury L David, Lawrence Matthew, Hu Wenzheng, Poloso Neil J
Research and External Scientific Innovation, Allergan Inc., Irvine, California 92612, United States.
Discovery Department, Selcia Ltd., Ongar, Essex, CM5 0GS, U.K.
ACS Pharmacol Transl Sci. 2020 Oct 26;3(6):1199-1210. doi: 10.1021/acsptsci.0c00118. eCollection 2020 Dec 11.
It has previously been reported that a prototypical compound (AGN 211377), which blocks pro-inflammatory prostanoid receptors (DP, DP, EP, EP FP, TP) and leaves open IP and EP receptors so that their anti-inflammatory properties could be exerted, produced superior inhibitory effects on cytokine release from human macrophages compared to cyclooxygenase (COX) inhibitors. This favorable activity profile translated into animal studies, with AGN 211377 exceeding the level of inhibition afforded by COX inhibition. AGN 211377 was not, however, a practical drug candidate, having poor bioavailability and cost of goods concerns. Compound (designated AGN 225660) represents a second-generation compound with an entirely different "druggable" core structure. Such a dramatic change in chemical scaffold created uncertainty with respect to matching the effects of AGN 211377. AGN 225660 inhibited RANTES, IL-8, and MCP-1 secretion by at least 50%, from TNFα activated human macrophages. Although AGN 225660 reduced TNFα-evoked MCP-1 release from human monocyte-derived macrophages, it increased LPS-induced MCP-1 secretion (up to 2-fold) from human monocyte-derived dendritic cells. However, AGN 225660 inhibited the release of IL12p 70 and IL-23 from human monocyte-derived dendritic cells stimulated by LPS by more than 70%. This effect of AGN 225660 was reproduced in part by the prototype compound AGN 211377 and a combination of selective DP, EP, EP, FP, and TP antagonists. These findings suggest important effects on T cell skewing and disease modification by this class of therapeutic agents. AGN 225660 exhibited good ocular bioavailability and was active in reducing ocular inflammation associated with phacoemulsification surgery, LPS, and arachidonic acid induced uveitis.
此前有报道称，一种原型化合物（AGN 211377）可阻断促炎性前列腺素受体（DP、DP、EP、EP、FP、TP），而使IP和EP受体保持开放，从而发挥其抗炎特性。与环氧化酶（COX）抑制剂相比，该化合物对人巨噬细胞释放细胞因子具有更强的抑制作用。这种良好的活性特征在动物研究中也得到了体现，AGN 211377的抑制水平超过了COX抑制作用。然而，AGN 211377并非一个实用的候选药物，因为其生物利用度差且存在商品成本问题。化合物（命名为AGN 225660）代表了具有完全不同“可成药”核心结构的第二代化合物。化学支架的这种巨大变化使得在匹配AGN 211377的效果方面产生了不确定性。AGN 225660可使肿瘤坏死因子α（TNFα）激活的人巨噬细胞分泌的调节激活正常T细胞表达和分泌的趋化因子（RANTES）、白细胞介素8（IL-8）和单核细胞趋化蛋白1（MCP-1）至少减少50%。尽管AGN 225660可减少TNFα诱导的人单核细胞衍生巨噬细胞释放MCP-1，但它却增加了脂多糖（LPS）诱导的人单核细胞衍生树突状细胞分泌MCP-1（高达2倍）。然而，AGN 225660可使LPS刺激的人单核细胞衍生树突状细胞释放白细胞介素12p70（IL12p70）和白细胞介素23（IL-23）减少70%以上。AGN 225660的这种作用部分可由原型化合物AGN 211377以及选择性DP、EP、EP、FP和TP拮抗剂的组合重现。这些发现表明这类治疗药物对T细胞偏向和疾病改善具有重要作用。AGN 225660具有良好 的眼部生物利用度，并且在减轻与超声乳化手术、LPS和花生四烯酸诱导的葡萄膜炎相关的眼部炎症方面具有活性。
