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

Abstract

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.

Evaluation of 1,2,3‐Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX‐770 and VX‐809

“… A) Structure of corrector 8 and C18 (VRT‐534) bearing the benzo[ d ][1,3]dioxole cyclopropane carboxamide pharmacophore. B) Targeted alkyne 9 and azide 10 to explore the viability of the 2,2‐difluorobenzo[ d ][1,3]dioxole cyclopropane 1,2,3‐triazole pharmacophore.…”

“…Design of 1,2,3-triazole analogues in the VX-809structural class AmongF 508del-CFTR correctors, the benzo[d] [1,3]dioxole cyclopropane carboxamide moiety has been maintained as an essentials tructural feature across otherwise diverse chemical scaffolds, suggesting that this moiety is ak ey pharmacophore for corrector efficacy.A ss een in the comparison of VX-809, VX-661, corrector 8 reported by AbbVie Pharmaceuticals (Figure 4A), [30] and the widely employed tool compound C18 (VRT-534, Figure 4A), [31,32] considerable structurally variability is tolerated within the amide nitrogen substituent provided that the benzo[d] [1,3]dioxole cyclopropanec arboxamide moiety is present. On the basis of this observation, we hypothesized that CuAACo ri sCC methods using 2,2-difluorobenzo[d] [1,3]dioxole cyclopropane alkyne 9 ( Figure 4B)h ave strong potential to develop an ew class of correctors, if the 2,2-difluorobenzo[d] [1,3]dioxole cyclopropane1 ,2,3-triazole can serve as as uitable pharmacophore for F508del-CFTR correction.…”

“…To investigate this question, we targeted the synthesis of 1,2,3-triazolec ontainingc orrector 11 showni nF igure 4B,w hich is ac lose structural analogueo fa mide-containing VX-809. [30] and C18 (VRT-534) [31,32] bearing the benzo[d] [1,3]dioxole cyclopropane carboxamide pharmacophore. B) Ta rgeted alkyne 9 and azide 10 to explore the viability of the 2,2-difluorobenzo[d] [1,3]dioxole cyclopropane 1,2,3-triazole pharmacophore.…”

CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials

“…However, a need remains for more effective treatments for CF subjects with F508del mutation, and novel doublet and triplet potentiator and corrector combinations are under clinical evaluation (NCT03525444, NCT03525574, NCT03447249, NCT03447262, NCT03500263). Class III gating mutations (e.g., G551D), which result in the failure of CFTR channels to function on the cell surface [5,15], are less common than the F508del mutation [16] and functioning can be partially restored with CFTR potentiators. However, as the majority of people with a gating mutation also have the F508del mutation on their second allele (83% in the USA [17] and 87% in Europe [18]), these patients may benefit from being treated with a corrector in addition to a potentiator.…”

“…GLPG2222 is a novel, potent CFTR corrector in development for the treatment of CF [15,19,20]. In primary bronchial epithelial cells from F508del homozygous subjects, GLPG2222 in combination with a potentiator partially restored CFTR function and was over 25-fold more potent than lumacaftor [15]. In phase 1 studies, GLPG2222 was well tolerated in healthy and CF subjects, and single-dose pharmacokinetics (PK) were similar in both populations [19,20].…”