PPQ-102

• CAT Number: I005534
• CAS Number: 931706-15-9
• Molecular Formula: C26H22N4O3
• Molecular Weight: 438.5
• Purity: ≥95%
• Synonyms: 6,7-Dihydro-7,9-dimethyl-6-(5-methyl-2-furanyl)-11-phenylpyrimido[4/’,5/’:3,4]pyrrolo[1,2-a]quinoxaline-8,10(5H,9)-dione
• Target: CFTR
• Solubility: DMSO: ≥ 52 mg/mL
• Storage: -20°C
• IC50: 90 nM
• InChI: InChI=1S/C26H22N4O3/c1-15-13-14-19(33-15)21-24-23-20(25(31)29(3)26(32)28(23)2)22(16-9-5-4-6-10-16)30(24)18-12-8-7-11-17(18)27-21/h4-14,21,27H,1-3H3
• InChIKey: MNOOVRNGPIWJDI-UHFFFAOYSA-N
• SMILES: CC1=CC=C(O1)C2C3=C4C(C(N(C)C(N4C)=O)=O)=C(C5=CC=CC=C5)N3C6=C(C=CC=C6)N2

PPQ-102 is a potent CFTR inhibitor which can completely inhibited CFTR chloride current with IC50 approximately 90 nM.


in vitro: The most potent compound, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido[4/’,5/’-3,4]pyrrolo[1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC(50) approximately 90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch-clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state [1]. The three gpSlc26 anion transporters exhibited distinct pharmacological profiles of (36)Cl(-) influx, including partial sensitivity to CFTR inhibitors Inh-172 and GlyH101, but only Slc26a11 was inhibited by PPQ-102 [2]. Airway epithelial NCI-H292 cells and primary cultures of noncystic fibrosis human airway epithelial cells were treated with cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors (CFTR-inh(172) or PPQ-102) or transfected with a CFTR small interfering (si)RNA with or without a selective epidermal growth factor receptor tyrosine kinase inhibitor [3].


in vivo: PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date [1].

Reference

[1]. Tradtrantip L, et al. Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model. J Med Chem. 2009 Oct 22;52(20):6447-55. 


[2]. Stewart AK, et al. SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization. Am J Physiol Cell Physiol. 2011 Aug;301(2):C289-303. 


[3]. Martin C, et al. CFTR dysfunction induces vascular endothelial growth factor synthesis in airway epithelium. Eur Respir J. 2013 Dec;42(6):1553-62.