Discovery of 4-[(2R,4R)-4-({[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic Acid (ABBV/GLPG-2222), a Potent Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Corrector for the Treatment of Cystic Fibrosis,Journal of Medicinal Chemistry

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Discovery of 4-[(2R,4R)-4-({[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic Acid (ABBV/GLPG-2222), a Potent Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Corrector for the Treatment of Cystic Fibrosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-05 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01339
Xueqing Wang ₁ , Bo Liu ₁ , Xenia Searle ₁ , Clinton Yeung ₁ , Andrew Bogdan ₁ , Stephen Greszler ₁ , Ashvani Singh ₁ , Yihong Fan ₁ , Andrew M Swensen ₁ , Timothy Vortherms ₁ , Corina Balut ₁ , Ying Jia ₁ , Kelly Desino ₁ , Wenqing Gao ₁ , Hong Yong ₁ , Chris Tse ₁ , Philip Kym ₁

Affiliation

Cystic fibrosis (CF) is a multiorgan disease of the lungs, sinuses, pancreas, and gastrointestinal tract that is caused by a dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial anion channel that regulates salt and water balance in the tissues in which it is expressed. To effectively treat the most prevalent patient population (F508del mutation), two biomolecular modulators are required: correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. Despite approved potentiator and potentiator/corrector combination therapies, there remains a high need to develop more potent and efficacious correctors. Herein, we disclose the discovery of a highly potent series of CFTR correctors and the structure–activity relationship (SAR) studies that guided the discovery of ABBV/GLPG-2222 (22), which is currently in clinical trials in patients harboring the F508del CFTR mutation on at least one allele.

中文翻译：

4-[（2 R，4 R）-4-（{[1-（2,2-二氟-1,3-苯并二恶唑-5-基）环丙基]羰基}氨基）-7-（二氟甲氧基）-的发现3,4-二氢-2 H-铬-2-基]苯甲酸（ABBV / GLPG-2222），一种有效的囊性纤维化跨膜电导调节剂（CFTR）校正剂，用于治疗囊性纤维化

囊性纤维化（CF）是肺，鼻窦，胰腺和胃肠道的多器官疾病，由囊性纤维化跨膜电导调节剂（CFTR）蛋白功能异常或缺乏引起，该蛋白是调节盐和水平衡的上皮阴离子通道在表达它的组织中。为了有效治疗最普遍的患者群体（F508del突变），需要两种生物分子调节剂：用于增加细胞表面CFTR水平的校正剂，以及允许CFTR通道有效打开的增强剂。尽管批准了增效剂和增效剂/校正剂组合疗法，但仍然非常需要开发更有效和有效的校正剂。在此处，22），目前正在对至少一个等位基因上带有F508del CFTR突变的患者进行临床试验。

更新日期：2018-01-05

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