Journal of Medicinal Chemistry p. 1436 - 1449 (2018)
Update date:2022-08-15
Topics:
Wang, Xueqing
Liu, Bo
Searle, Xenia
Yeung, Clinton
Bogdan, Andrew
Greszler, Stephen
Singh, Ashvani
Fan, Yihong
Swensen, Andrew M
Vortherms, Timothy
Balut, Corina
Jia, Ying
Desino, Kelly
Gao, Wenqing
Yong, Hong
Tse, Chris
Kym, Philip
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.
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