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Synthesis and biological evaluation of thiazole derivatives on basic defects underlying cystic fibrosis.

Authors
  • Pesce, Emanuela1
  • Pedemonte, Nicoletta1
  • Leoni, Alberto2
  • Locatelli, Alessandra2
  • Morigi, Rita3
  • 1 U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy. , (Italy)
  • 2 Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy. , (Italy)
  • 3 Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy. Electronic address: [email protected] , (Italy)
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Aug 09, 2020
Volume
30
Issue
21
Pages
127473–127473
Identifiers
DOI: 10.1016/j.bmcl.2020.127473
PMID: 32784089
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Cystic fibrosis is a genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator gene, encoding for CFTR protein. The most frequent mutation is the deletion of phenylalanine at position 508 (F508del), which leads to distinct defects in channel gating and cellular processing. In last years, several thiazole containing small molecules, endowed with dual F508del-CFTR modulator activity, proved to be able to target these defects. In search of new chemical entities able to restore CFTR function, we designed and synthesized a small series of sixteen thiazole derivatives. The designed compounds were studied as correctors and potentiators of F508del-CFTR. Although none of the molecules showed significant corrector activity, compounds 10 and 11 exhibited potentiator effects, thus allowing to determine some basic structural features which enable to obtain F508del-CFTR potentiator activity. In silico ADME studies showed that these derivatives obey Lipinski's rule of five and are expected to be orally bioavailable. Therefore, these molecules may represent a good starting point for the design of analogues endowed with improved CFTR potentiator activity and a good pharmacokinetic profile. Copyright © 2020 Elsevier Ltd. All rights reserved.

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