国家1类新药艾瑞昔布的研制

Discovery of imrecoxib

基于药效团的分子设计是模拟创新药物研究的重要方法。基于已有COX-2抑制剂的结构构建了药效团,并根据药效团特征及其分布,设计了以不饱和吡咯烷酮为骨架的COX-2抑制剂,体外评价了化合物对COX-2和COX-1的抑制活性。为了避免COX-2高选择性抑制剂引起心血管事件的风险,提出了对COX酶适度抑制的策略,在抑制引起炎症的COX-2酶的前提下,不对其过分抑制,以保持COX-2和COX-1在体内功能上的平衡,以此作为优化和选择候选化合物的原则,进而通过动物抗炎模型试验、耐受性试验和大鼠的药代动力学试验,综合评价两个候选化合物的药效学、药代动力学、物化性质和制备成本等因素,选定艾瑞昔布为进入开发阶段的候选药物,经临床前的药学和生物学的全面试验,进行了临床Ⅰ,Ⅱ和Ⅲ期试验研究,证明是治疗人骨关节炎的安全有效的药物,遂于2011年5月获得SFDA的批准。

Pharmacophore-based drug design is one of the important approaches for follow-on drug discovery. A pharmacophore model was first constructed from known COX-2 inhibitors, and then, two series of unsaturated pyrrolinone compounds were designed, synthesized and evaluated in vitro for the inhibitory effects on COX-2 and COX-1 enzymes. In order to avoid cardiovascular risks induced by high selective COX-2 inhibitors, the project advocated the conception of ＂moderate selectivity＂ for COX-2 enzyme. Virtually, instead of highly selective COX-2 inhibitors, carefully balanced inhibition to both COX-1 and COX-2 was pursued to maintain the homeostasis of the two enzymes in the body, which is presumably critical to normal functions of the cardiovascular system. According- ly, potent molecules with moderate selectivity were further evaluated in vivo for their anti-inflammatory activity in animal models. Sub-acute toxicity trials and pharmacokinetic studies on rats were successively conducted. From the comprehensive consideration of PD, PK, safety, and preparation cost, a drug candidate, Imrecoxib, was selected for pre-clinical trails and the phases I, II, and III clinical investigations. Imrecoxib has been proved to be an effectire and safe medicine for the treatment of osteoarthritis,