Article

Stimulation of Wild-Type, F508del- and G551D-CFTR Chloride Channels by Non-Toxic Modified pyrrolo[2,3-b]pyrazine Derivatives.

Institut de Physiologie et Biologie Cellulaires, UMR 6187, Université de Poitiers CNRS, Poitiers, France.
Frontiers in Pharmacology 01/2011; 2:48. DOI: 10.3389/fphar.2011.00048
Source: PubMed

ABSTRACT Cystic fibrosis (CF) is a major inherited disorder involving abnormalities of fluid and electrolyte transport in a number of different organs due to abnormal function of cystic fibrosis transmembrane conductance regulator (CFTR) protein. We recently identified a family of CFTR activators, which contains the hit: RP107 [7-n-butyl-6-(4-hydroxyphenyl)[5H]-pyrrolo[2,3-b]pyrazine]. Here, we further evaluated the effect of the chemical modifications of the RP107-OH radical on CFTR activation. The replacement of the OH radical by a fluorine atom at position 2 (RP193) or 4 (RP185) significantly decreased the toxicity of the compounds without altering the ability to activate CFTR, especially for RP193. The non-toxic compound RP193 has no effect on cAMP production but stimulates the channel activity of wild-type CFTR in stably transfected CHO cells, in human bronchial epithelial NuLi-1 cells, and in primary culture of human bronchial epithelial cells (HBEC). Whole-cell and single patch-clamp recordings showed that RP193 induced a linear, time- and voltage-independent current, which was fully inhibited by two different and selective CFTR inhibitors (CFTRinh-172 and GP(inh)5a). Moreover, RP193 stimulates CFTR in temperature-rescued CuFi-1 (F508del/F508del) HBEC and in CHO cells stably expressing G551D-CFTR. This study shows that it is feasible to reduce cytotoxicity of chemical compounds without affecting their potency to activate CFTR and to rescue the class 2 F508del-CFTR and class 3 G551D-CFTR CF mutant activities.

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    ABSTRACT: Introduction: Cystic fibrosis (CF) is the most prevalent, recessively inherited, disease in the western world. It is characterized by gene mutations in CF transmembrane conductance regulator (CFTR), a transmembrane ion channel that is responsible for chloride secretion in the airway passages. Although much is known about the defects in CFTR and the consequences of these mutations, CF therapy currently focuses on the secondary outcomes and symptoms of the disease. However, developments in CFTR modulators may bring about new therapeutic options. Areas covered: The authors discuss CFTR defects, as a molecular basis, before presenting and discussing CFTR modulators including correctors and potentiators. Specifically, the authors review promising CFTR modulators currently in preclinical and clinical development along with their medicinal chemistry and structure-activity relationships (SARs) and their in vitro and in vivo pharmacology. Expert opinion: Although the development of CFTR-targeting agents has little access to structural information from crystal structures, several promising compounds have been discovered so far. Advanced virtual models of CFTR and high-throughput assays have helped the developmental programs. While Ivacaftor, the first of the CFTR potentiators, has now reached clinical use, CFTR corrector development has not been successful thus far. However, intense research of the mutation F508del, the mutation considered the most frequent in CF, could provide new causal treatment options in the future. Furthermore, the eventual synergy with multiple correctors may bring further success. CFTR modulators provide a new personalized therapeutic option where CF therapy is based on the mutations patients carry rather than by simply their symptoms.
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