| Autor: |
Coffman KC; Department of Chemistry, University of California , One Shields Avenue, Davis, California 95616, United States., Nguyen HH, Phuan PW, Hudson BM, Yu GJ, Bagdasarian AL, Montgomery D, Lodewyk MW, Yang B, Yoo CL, Verkman AS, Tantillo DJ, Kurth MJ |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2014 Aug 14; Vol. 57 (15), pp. 6729-38. Date of Electronic Publication: 2014 Jul 25. |
| DOI: |
10.1021/jm5007885 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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