2018年首创性小分子药物研究实例浅析

First-in-class small molecule drugs in 2018

首创性(first-in-class)药物是使用全新的、独特的作用机制或靶向于某个全新的候选靶标来治疗某种疾病的药物,其研发理念和过程不同于跟随性药物(me too,me better)。2018年,美国食品药品监督管理局(FDA)共批准上市了59个全新药物,打破了1993年批准53个新药的历史记录。获批的新药中,小分子药物以64%占据较大比例。在获批的34个小分子新药中,有9个是首创性的小分子药物,这对后续的药物研发具有里程碑式的重要意义。其中包括全球首个作用于Hedgehog信号通路的Smo小分子抑制剂格拉德吉;首个靶向于突变型IDH1的小分子抑制剂艾伏尼布;首个抗天花病毒的p37蛋白小分子抑制剂替韦立马;首个靶向于cap-依赖型核酸内切酶的抗流感药物玛巴洛沙韦;首个靶向于GnRH-R治疗子宫内膜异位症的小分子药物艾拉戈克钠等。首创性的药物研发往往需要经历非常坎坷的研发过程,而成功的首创性药物多数也都成为重磅炸弹级的明星药物。本文选取2018年批准的具有代表性的首创性小分子药物研究实例,浅析其研发过程,为更多首创药物的研发提供研究借鉴及研发思路。

In 2018,FDA approved 59 kinds of new drugs in all,breaking the record of 53 set in 1993.There were 34 types of small molecule drugs,which accounted for 64% of the whole new drugs.Of these 34 new small molecule drugs,9 first-in-class ones marked a milestone for the subsequent drug discovery and development.These include Glasdegib,the world’s first small molecule inhibitor targeting Smo through Hedgehog signaling pathway;Ivosidenib,the first small molecule inhibitor targeting mutant IDH1;Tecovirimat,the first small molecule drug for anti-variola virus therapy through targeting p37;Baloxavir marboxil,the first anti-flu drug targeting cap-dependent endonuclease;Elagolix sodium,the first small molecule inhibitor in treating endometriosis by targeting GnRH-R,etc.The research and development of first-in-class drugs is always full of obstacles and challenges.However,once they were successfully recognized as the "heavy bomb" drugs,they would become huge benefits.This article chose the representative first-in-class small molecule drugs that were approved in 2018 as examples to analyze their development processes in an attempt to provide guidance for the research and development of more first-in-class drugs.