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Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-25 , DOI: 10.1021/acs.jmedchem.3c01790 Mathieu Pizzonero 1 , Rhalid Akkari 1 , Xavier Bock 1 , Romain Gosmini 1 , Elsa De Lemos 1 , Béranger Duthion 1 , Gregory Newsome 1 , Thi-Thu-Trang Mai 1 , Virginie Roques 1 , Hélène Jary 1 , Jean-Michel Lefrancois 1 , Laetitia Cherel 1 , Vanessa Quenehen 1 , Marielle Babel 1 , Nuria Merayo 1 , Natacha Bienvenu 1 , Oscar Mammoliti 2 , Ghjuvanni Coti 2 , Adeline Palisse 2 , Marlon Cowart 3 , Anurupa Shrestha 3 , Stephen Greszler 3 , Steven Van Der Plas 2 , Koen Jansen 2 , Pieter Claes 2 , Mia Jans 2 , Maarten Gees 2 , Monica Borgonovi 1 , Gert De Wilde 2 , Katja Conrath 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-25 , DOI: 10.1021/acs.jmedchem.3c01790 Mathieu Pizzonero 1 , Rhalid Akkari 1 , Xavier Bock 1 , Romain Gosmini 1 , Elsa De Lemos 1 , Béranger Duthion 1 , Gregory Newsome 1 , Thi-Thu-Trang Mai 1 , Virginie Roques 1 , Hélène Jary 1 , Jean-Michel Lefrancois 1 , Laetitia Cherel 1 , Vanessa Quenehen 1 , Marielle Babel 1 , Nuria Merayo 1 , Natacha Bienvenu 1 , Oscar Mammoliti 2 , Ghjuvanni Coti 2 , Adeline Palisse 2 , Marlon Cowart 3 , Anurupa Shrestha 3 , Stephen Greszler 3 , Steven Van Der Plas 2 , Koen Jansen 2 , Pieter Claes 2 , Mia Jans 2 , Maarten Gees 2 , Monica Borgonovi 1 , Gert De Wilde 2 , Katja Conrath 2
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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. This epithelial anion channel regulates the active transport of chloride and bicarbonate ions across membranes. Mutations result in reduced surface expression of CFTR channels with impaired functionality. Correctors are small molecules that support the trafficking of CFTR to increase its membrane expression. Such correctors can have different mechanisms of action. Combinations may result in a further improved therapeutic benefit. We describe the identification and optimization of a new pyrazolol3,4-bl pyridine-6-carboxylic acid series with high potency and efficacy in rescuing CFTR from the cell surface. Investigations showed that carboxylic acid group replacement with acylsulfonamides and acylsulfonylureas improved ADMET and PK properties, leading to the discovery of the structurally novel co-corrector GLPG2737. The addition of GLPG2737 to the combination of the potentiator GLPG1837 and C1 corrector 4 led to an 8-fold increase in the F508del CFTR activity.
中文翻译：
GLPG2737 的发现，一种有效的 CFTR 2 型校正剂，与增效剂和 1 型辅助校正剂相结合，用于治疗囊性纤维化
囊性纤维化 (CF) 是由 CF 跨膜电导调节蛋白 (CFTR) 突变引起的。这种上皮阴离子通道调节氯离子和碳酸氢根离子跨膜的主动转运。突变导致 CFTR 通道表面表达减少，功能受损。校正剂是支持 CFTR 运输以增加其膜表达的小分子。此类校正器可以具有不同的作用机制。组合可能会导致进一步改善的治疗效果。我们描述了新型吡唑醇3,4-bl吡啶-6-羧酸系列的鉴定和优化，该系列在从细胞表面拯救CFTR方面具有高效能和功效。研究表明，用酰基磺酰胺和酰基磺酰脲类取代羧酸基团可改善 ADMET 和 PK 特性，从而发现了结构新颖的辅助校正剂 GLPG2737。将 GLPG2737 添加到增效剂 GLPG1837 和 C1 校正剂4的组合中，导致 F508del CFTR 活性增加 8 倍。
更新日期：2024-03-25
中文翻译：
GLPG2737 的发现，一种有效的 CFTR 2 型校正剂，与增效剂和 1 型辅助校正剂相结合，用于治疗囊性纤维化
囊性纤维化 (CF) 是由 CF 跨膜电导调节蛋白 (CFTR) 突变引起的。这种上皮阴离子通道调节氯离子和碳酸氢根离子跨膜的主动转运。突变导致 CFTR 通道表面表达减少，功能受损。校正剂是支持 CFTR 运输以增加其膜表达的小分子。此类校正器可以具有不同的作用机制。组合可能会导致进一步改善的治疗效果。我们描述了新型吡唑醇3,4-bl吡啶-6-羧酸系列的鉴定和优化，该系列在从细胞表面拯救CFTR方面具有高效能和功效。研究表明，用酰基磺酰胺和酰基磺酰脲类取代羧酸基团可改善 ADMET 和 PK 特性，从而发现了结构新颖的辅助校正剂 GLPG2737。将 GLPG2737 添加到增效剂 GLPG1837 和 C1 校正剂4的组合中，导致 F508del CFTR 活性增加 8 倍。
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