The discovery and development of gefapixant
The discovery and development of gefapixant
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DOI：
10.1016/j.autneu.2021.102859
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发表时间：
2021-08-14
影响因子：
2.7
通讯作者：
Gever, Joel R.
中科院分区：
文献类型：
--
作者：
Ford, Anthony P.;Dillon, Michael P.;Gever, Joel R.
吉发哌克生是一种化合物的批准通用名，也称为MK-7264，在此之前是AF-219和RO-4926219。它是第一种临床开发的三聚体离子型嘌呤能受体P2 X3亚型拮抗剂，三聚体离子型嘌呤能受体是ATP门控兴奋性离子通道家族，对人P2 X3同源三聚体通道显示出纳摩尔效力，对缺乏P2 X3亚基的相关通道基本上没有活性。作为第一个进入临床研究的P2 X3拮抗剂，它现在已经进展到成功完成治疗咳嗽的III期研究的地步，并且美国FDA正在审查NDA申请，用于治疗难治性慢性咳嗽或原因不明的慢性咳嗽。该分子是在位于加州帕洛阿尔托的罗氏制药公司的实验室中发现的，但随后临床开发继续进行，形成了传入制药公司，目的是确定这种新机制的最佳治疗适应症，并建立在选定的最佳患者群体中开发的临床计划。Geoff Burnstock是P2 X3项目近二十年的发现和开发的密切合作者和顾问。默克公司的研究实验室已经通过后期临床研究对吉法匹生进行了进展，股份有限公司、Kenilworth，NJ，USA（MRL;在2016年收购Afferent之后），一旦获得监管机构的授权，可能会将该产品商业化。
Gefapixant is the approved generic name for a compound also known as MK-7264, and prior to that AF-219 and RO-4926219. It is the first-in-class clinically developed antagonist for the P2X3 subtype of trimeric ionotropic purinergic receptors, a family of ATP-gated excitatory ion channels, showing nanomolar potency for the human P2X3 homotrimeric channel and essentially no activity at related channels devoid of P2X3 subunits. As the first P2X3 antagonist to have progressed into clinical studies it has now progressed to the point of successful completion of Phase 3 investigations for the treatment of cough, and the NDA application is under review with US FDA for treatment of refractory chronic cough or unexplained chronic cough. The molecule was discovered in the laboratories of Roche Pharmaceuticals in Palo Alto, California, but clinical development then continued with the formation of Afferent Pharmaceuticals for the purpose of identifying the optimal therapeutic indication for this novel mechanism and establishing a clinical plan for development in the optimal patient populations selected. Geoff Burnstock was a close collaborator and advisor to the P2X3 program for close to two decades of discovery and development. Progression of gefapixant through later stage clinical studies has been conducted by the research laboratories of Merck & Co., Inc., Kenilworth, NJ, USA (MRL; following acquisition of Afferent in 2016), who may commercialize the product once authorization has been granted by regulatory authorities.