国家1类新药艾瑞昔布的研制

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。

Discovery of imrecoxib

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.Accordingly,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 effective and safe medicine for the treatment of osteoarthritis,and approved by the SFDA for Chinese market.