Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis.
Scanio MJC, Searle XB, Liu B, Koenig JR, Altenbach R, Gfesser GA, Bogdan A, Greszler S, Zhao G, Singh A, Fan Y, Swensen AM, Vortherms T, Manelli A, Balut C, Jia Y, Gao W, Yong H, Schrimpf M, Tse C, Kym P, Wang X.
Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the <i>CFTR</i> gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2<i>S</i>,3<i>R</i>,4<i>S</i>,5<i>S</i>)-3-(<i>tert</i>-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((<i>S</i>)-tetrahydro-2<i>H</i>-pyran-2-carbonyl)-5-(<i>o</i>-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.