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Discovery of GLPG2451, a Novel Once Daily Potentiator for the Treatment of Cystic Fibrosis
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2021-01-05 , DOI: 10.1021/acs.jmedchem.0c01796
Steven E Van der Plas 1 , Hans Kelgtermans 1 , Oscar Mammoliti 1 , Christel Menet 1 , Giovanni Tricarico 1 , Ann De Blieck 1 , Caroline Joannesse 1 , Tom De Munck 1 , Dominique Lambin 1 , Marlon Cowart 2 , Sebastien Dropsit 1 , Sebastien L X Martina 1 , Maarten Gees , Anne-Sophie Wesse , Katja Conrath 1 , Martin Andrews 1
Affiliation  

Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.

中文翻译:

发现 GLPG2451,一种用于治疗囊性纤维化的新型每日一次增效剂

囊性纤维化 (CF) 是一种威胁生命的隐性遗传疾病,由编码囊性纤维化跨膜电导调节剂 (CFTR) 的基因突变引起。随着 Ivacaftor 和 Lumacaftor 的发现,已经表明给予一种或多种小分子可以部分恢复 CFTR 功能。校正剂是增强细胞表面 CFTR 量的小分子,而增效剂可改善 CFTR 通道的门控功能。在此,我们描述了一种新型增效剂系列的发现和优化。支架跳跃,专注于保留不同的分子内接触,在整个发现过程中至关重要,以确定一个没有遗传毒性责任的新系列。从该系列中,根据其药代动力学特性选择了临床候选物 GLPG2451,
更新日期:2021-01-14
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