Journal of Medicinal Chemistry p. 458 - 473 (2017)
Update date:2022-08-17
Topics:
Vu, Chi B.
Bridges, Robert J.
Pena-Rasgado, Cecilia
Lacerda, Antonio E.
Bordwell, Curtis
Sewell, Abby
Nichols, Andrew J.
Chandran, Sachin
Lonkar, Pallavi
Picarella, Dominic
Ting, Amal
Wensley, Allison
Yeager, Maisy
Liu, Feng
A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.
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