Constrained Bithiazoles: Small Molecule Correctors of Defective ΔF508–CFTR Protein Trafficking

Abstract

Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508–CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.

High-Potency Phenylquinoxalinone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activators

“…Motivated by our prior findings that constrained rings can enhance the activity of a CFTR corrector, 15 we next examined two different types of constrained analogs (Scheme 4) with hindered rotation of the N 1 -alkyl group ( 16 and 20 ) or phenyl ring ( 22 and 23 ). As previously shown, the N -acetylated version of 4 has very low activity; 4 we therefore attempted to synthesize 16 without an N -acyl group, but both deacylation of 16 and condensation with 5-nitroisatin failed.…”

ΔF508-CFTR correctors: Synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles

“…Our previous work, 5–7 especially that with tethered bithiazoles such as 1a , provides circumstantial evidence in support of a “U-shaped” bioactive conformation (Figure 2), rigidified in part by S•••lone pair interactions. 6,25 The overall lowest energy conformer found for each compound, along with the lowest energy U-shaped conformer (both in water) are shown in Table 2 (see Supporting Information for additional details, including interatomic distances).…”

“…6 Indeed, the s-cis coplanar conformation, as exemplified by bithiazole 1a wherein the two thiazole rings are constrained by an alkyl chain, is required for corrector activity. 6,7 …”

“…Our previous work indicates that the conformation about the inter-ring bond (see ~coplanar bisazole rings in Figure 2) correlates with activity as constrained 1a is more active than unconstrained 1 . 5–7 It therefore appears that access to the conformational control elements highlighted in Figure 2 are required for activity.…”

Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems

“…In addition to addressing the disease symptomatically, a personalized medicinal approach targeting the specific protein defect has also been used recently in many studies in the CF field [ 34 , 35 , 36 , 37 , 38 ].…”