产品号 #100-0554_C
抑制囊性纤维化跨膜传导调节剂（CFTR）
概述
CFTR(inh)-172是囊性纤维化跨膜传导调节剂（CFTR）的选择性和可逆噻唑烷酮抑制剂；Ki = 300 nM；Ma等人)。CFTR是一种氯离子通道，参与许多上皮组织（如气道和肠）的液体分泌（Ma等）。CFTR基因缺陷改变离子转运，可导致囊性纤维化(Dalli等人；Ma等人)。腹腔注射CFTR(inh)-172可抑制霍乱毒素诱导的肠液分泌（Ma et al.）。
疾病模型
·减缓小鼠多囊肾病的囊肿生长（Yang等）。
Alternative Names
Cystic fibrosis transmembrane conductance regulator inhibitor 172; CFTR Inhibitor-172
Cell Type
Airway Cells, Intestinal Cells
Area of Interest
Disease Modeling, Epithelial Cell Biology
CAS Number
307510-92-5
Chemical Formula
C18H10F3NO3S2
Molecular Weight
409.4 g/mol
Purity
≥ 98%
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
Resources and Publications
Educational Materials (3)
Publications (3)
CFTR inhibition provokes an inflammatory response associated with an imbalance of the annexin A1 pathway. The American journal of pathology 2010 jul
Abstract
Cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, is characterized by chronic bacterial infections and inflammation in the lung. Having previously shown that deletion of CFTR is associated with lower expression of the endogenous anti-inflammatory protein Annexin A1 (AnxA1), we investigated further this possible functional connection using a validated CFTR inhibitor. Treatment of mice with the CFTR inhibitor-172 (CFTR(172)) augmented the acute peritonitis promoted by zymosan, an effect associated with lower AnxA1 levels in peritoneal cells. Similar results were obtained with another, chemically distinct, CFTR inhibitor. The pro-inflammatory effect of CFTR(172) was lost in AnxA1(-/-), as well as CFTR(-/-) mice. Importantly, administration of hrAnxA1 and its peptido-mimetic to CFTR(-/-) animals or to animals treated with CFTR(172) corrected the exaggerated leukocyte migration seen in these animals. In vitro assays with human Polymorphonuclear leukocyte (PMN) demonstrated that CFTR(172) reduced cell-associated AnxA1 by promoting release of the protein in microparticles. We propose that the reduced impact of the counterregulatory properties of AnxA1 in CF cells contributes to the inflammatory phenotype characteristic of this disease. Thus, these findings provide an important insight into the mechanism underlying the inflammatory disease associated with CFTR inhibition while, at the same time, providing a novel pharmacological target for controlling the inflammatory phenotype of CF.
Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. Journal of the American Society of Nephrology : JASN 2008 jul
Abstract
Cyst expansion in polycystic kidney disease (PKD) involves progressive fluid accumulation, which is believed to require chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Herein is reported that small-molecule CFTR inhibitors of the thiazolidinone and glycine hydrazide classes slow cyst expansion in in vitro and in vivo models of PKD. More than 30 CFTR inhibitor analogs were screened in an MDCK cell model, and near-complete suppression of cyst growth was found by tetrazolo-CFTR(inh)-172, a tetrazolo-derived thiazolidinone, and Ph-GlyH-101, a phenyl-derived glycine hydrazide, without an effect on cell proliferation. These compounds also inhibited cyst number and growth by {\textgreater}80{\%} in an embryonic kidney cyst model involving 4-d organ culture of embryonic day 13.5 mouse kidneys in 8-Br-cAMP-containing medium. Subcutaneous delivery of tetrazolo-CFTR(inh)-172 and Ph-GlyH-101 to neonatal, kidney-specific PKD1 knockout mice produced stable, therapeutic inhibitor concentrations of {\textgreater}3 microM in urine and kidney tissue. Treatment of mice for up to 7 d remarkably slowed kidney enlargement and cyst expansion and preserved renal function. These results implicate CFTR in renal cyst growth and suggest that CFTR inhibitors may hold therapeutic potential to reduce cyst growth in PKD.
Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. The Journal of clinical investigation 2002 dec
Abstract
Secretory diarrhea is the leading cause of infant death in developing countries and a major cause of morbidity in adults. The cystic fibrosis transmembrane conductance regulator (CFTR) protein is required for fluid secretion in the intestine and airways and, when defective, causes the lethal genetic disease cystic fibrosis. We screened 50,000 chemically diverse compounds for inhibition of cAMP/flavone-stimulated Cl(-) transport in epithelial cells expressing CFTR. Six CFTR inhibitors of the 2-thioxo-4-thiazolidinone chemical class were identified. The most potent compound discovered by screening of structural analogs, CFTR(inh)-172, reversibly inhibited CFTR short-circuit current in less than 2 minutes in a voltage-independent manner with K(I) approximately 300 nM. CFTR(inh)-172 was nontoxic at high concentrations in cell culture and mouse models. At concentrations fully inhibiting CFTR, CFTR(inh)-172 did not prevent elevation of cellular cAMP or inhibit non-CFTR Cl(-) channels, multidrug resistance protein-1 (MDR-1), ATP-sensitive K(+) channels, or a series of other transporters. A single intraperitoneal injection of CFTR(inh)-172 (250 micro g/kg) in mice reduced by more than 90{\%} cholera toxin-induced fluid secretion in the small intestine over 6 hours. Thiazolidinone CFTR inhibitors may be useful in developing large-animal models of cystic fibrosis and in reducing intestinal fluid loss in cholera and other secretory diarrheas.
更多信息
| Molecular Weight | 409.4 g/mol |
|---|---|
| Alternative Names | Cystic fibrosis transmembrane conductance regulator inhibitor 172; CFTR Inhibitor-172 |
| Cas Number | 307510-92-5 |
| Chemical Formula | C18H10F3NO3S2 |
| Purity | ≥ 98% |
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