2019年首创性小分子药物研究实例浅析

First-in-class small molecule drugs in 2019

首创性(first-in-class)药物的研发需要发现全新的候选靶标、生物机制和药物分子,耗时长、投入大、风险高,极具挑战性。成功的首创性药物不仅能成为疾病治疗的新策略,往往也能提供新颖的药物设计方法和研究思路。2019年,美国食品药品监督管理局(FDA)共批准上市了48个全新药物,小分子药物依然占据主流。其中包括多个首创性的小分子药物,例如首个用于治疗产后抑郁症的GABAA受体正向调节剂布瑞诺龙(Brexanolone),首个通过抑制核转运体XPO1治疗复发难治型多发性骨髓瘤的药物塞利尼索(Selinexor),首个通过抑制Na+/H+交换器NHE3治疗肠易激综合征的药物替那帕诺(Tenapanor),首个通过选择性激活5HT1F受体治疗偏头痛的药物拉米地坦(Lasmiditan)等。以上首创性药物的研发过程各具特点,设计思路新颖独特,本文通过浅析其中3例的研发背景、研发过程和治疗应用,以期为更多的首创性药物提供研究借鉴。

New candidate targets,biological mechanisms as well as small-molecules are significant factors in the research and development of first-in-class drugs,which is a challenging process with a large amount of time and money devoted as well as high risks.A successful first-in-class drug can not only become a new strategy for disease treatment but can also offer innovative research ideas for the design of drugs.The Food and Drug Adminis‐tration(FDA)approved 48 new drugs to the market in 2019,among which small-molecule drugs still predominated,containing several first-in-class drugs.Brexanolone,for example,is the first positive modulator of GABAAreceptor for the treatment of postpartum depression;Selinexor is the first small-molecule drug to treat recurrent refractory multiple myeloma by inhibiting exportin(XPO1);Tenapanor is the first sodium/proton exchanger type 3(NHE3)inhibitor that can treat irritable bowel syndrome;Lasmiditan is the first approved agonist with selectivity for 5-HT1F,treating migraines.The research and development processes of the first-in-class drugs mentioned above are distinctive from each other with uniqueness and innovation.In this review,we briefly analyze the background and process of the research and development of three typical cases as well as their therapeutic applications in an attempt to offer some help for the future development of first-in-class drugs.