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. 2024 Apr 11;67(7):5216-5232.
doi: 10.1021/acs.jmedchem.3c01790. Epub 2024 Mar 25.

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

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
Affiliations

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

Mathieu Pizzonero et al. J Med Chem. .

Abstract

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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): M.P., R.A., X.B., R.G., E.D.L., B.D., G.N., T.-T.-T.M., V.R., H.J., J.M.L., L.C., V.Q., M.B., N.M., N.B., O.M., G.C., A.P., S.V.D.P., K.J., P.C., M.J., M.G., M.B., G.D.W., and K.C. were employees of Galapagos at the time this work was completed. M.C., A.S., and S.G. are employees of AbbVie Inc., who collaborated with Galapagos in developing the molecule.

Figures

Figure 1
Figure 1
Structures of existing potentiators (1 and 3) and correctors (2, 4, and 5).
Figure 2
Figure 2
Plot of CSE HRP potency (X-axis, EC50 [nM]) and CSE HRP efficacy (Y-axis, % max activation) for acid (red), acylsulfonylurea (blue), and acylsulfonamide (yellow) analogues.
Figure 3
Figure 3
TECC current measurement assay in primary CF derived HBE cells (current induced after FSK stimulation after 24 h of incubation with correctors and potentiators). (A) Dose response of GLPG2737 in combination with 1 μM potentiator GLPG1837 and 0.15 μM corrector 4. (B) Comparison of a dose response for GLPG1837 in combination with 1 μM compound 52 + 0.15 μM C1 corrector 4 or only corrector 4.
Scheme 1
Scheme 1
a) 130–170 °C. 3–40 h, (54a: 67%, 54b: 95%); b) Phenyl dichlorophosphate. 170 °C. 15–21 h, (55a: 75%, 55b: 85%); c) CO(g). Pd(dppf)Cl2.DCM. sodium acetate. 1,4-dioxane. MeOH. 40–60 °C. 2–40 h, (56a: 58%, 56b: 63%); d) Amine. DIPEA or NEt3. MeCN or DMSO. 50–130 °C, (46–94%); e) NaOH or LiOH. H2O. MeOH and/or THF or dioxane. rt to 70 °C, (79–100%); f) EDC.HCl. corresponding nucleophile DMAP. DCM or THF or MeCN. rt. 20 h (30–80%) or CDI. DMF corresponding nucleophile. DBU. Rt (49: 100%, 52: 67%).
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References

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