931706-15-9

Basic information

• Product Name: PPQ-102
• Synonyms: PPQ-102;PPQ-102, CFTR Inhibitor;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;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 PPQ-102;PPQ-102 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;PPQ 102, >=98%;7,9-Dimethyl-6-(5-methylfuran-2-yl)-11-phenyl-5,6-dihydropyrimido[4',5':3,4]pyrrolo[1,2-a]quin
• CAS NO: 931706-15-9
• Molecular Formula: C₂₆H₂₂N₄O₃
• Molecular Weight: 438.49
• Product Categories: Inhibitors
• Mol File: 931706-15-9.mol
• Article Data: 2

Chemical Properties

• Melting Point: >300℃ (ethanol )
• Boiling Point: 648.7±65.0 °C(Predicted)
• Appearance: /
• Density: 1.39±0.1 g/cm3(Predicted)
• Storage Temp.: -20C
• PKA: 1.00±0.40(Predicted)
• CAS DataBase Reference: PPQ-102(CAS DataBase Reference)
• NIST Chemistry Reference: PPQ-102(931706-15-9)
• EPA Substance Registry System: PPQ-102(931706-15-9)

Safety Data

• Hazardous Substances Data: 931706-15-9(Hazardous Substances Data)

Usage

General Description

A cell-permeable pyrimido-pyrrolo-quinoxalinedione (PPQ) compound that targets the intracellular nucleotide binding domain(s) of CFTR and inhibits CFTR-mediated chloride current in a reversible and voltage-independent manner. Single channel recordings of CFTR-expressing FRT cells upon forskolin (Cat. No. 344270) and IBMX (Cat. No. 410957) stimulation indicate that the nature of PPQ-102 inhibition is due to a stabilization of the channels in a closed state (7.8- vs. 0.4-fold increase of mean channel close vs. open time, respectively, with 1 μM PPQ-102). PPQ-102 at 5 μM is shown to completely prevent Sp-8-Br-cAMP- (Cat. No. 116818) induced cysts formation and reduce the size of preformed cysts in an ex vivo murine neonatal kidney organ culture.

Upstream product

• 443667-38-7 5-benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 
• 444058-30-4 5-benzoyl-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione 
• 13509-52-9 1,3,6-trimethyluracil 
• 626-48-2 6-Methyluracil 
• 620-02-0 5-Methylfurfural 
• 433971-83-6 6-(2-aminophenyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione 

Downstream Products

• 1192478-29-7 N-(2-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)phenyl)-5-methylfuran-2-carboxamide 
• 1314872-75-7 7,9-dimethyl-6-(5-methylfuran-2-yl)-5-nitroso-11-phenyl-5,6-dihydropyrimido[4',5':3,4]pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione 
• 1314872-74-6 5-acetyl-7,9-dimethyl-6-(5-methylfuran-2-yl)-11-phenyl-5,6-dihydropyrimido[4',5':3,4]pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione 
• 1314872-72-4 7,9-dimethyl-6-(5-methylfuran-2-yl)-5-(methylsulfonyl)-11-phenyl-5,6-dihydropyrimido[4',5':3,4]pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione 
• 1314872-73-5 5-(2-chloroacetyl)-7,9-dimethyl-6-(5-methylfuran-2-yl)-11-phenyl-5,6-dihydropyrimido[4',5':3,4]pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione 

Relevant articles and documents

Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease

We previously reported the discovery of pyrimido-pyrrolo-quinoxalinedione (PPQ) inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and showed their efficacy in an organ culture model of polycystic kidney disease (PKD) (J. Med. Chem. 2009, 52, 6447-6455). Here, we report related benzopyrimido-pyrrolo-oxazinedione (BPO) CFTR inhibitors. To establish structure-activity relationships and select lead compound(s) with improved potency, metabolic stability, and aqueous solubility compared to the most potent prior compound 8 (PPQ-102, IC50 ～ 90 nM), we synthesized 16 PPQ analogues and 11 BPO analogues. The analogues were efficiently synthesized in 5-6 steps and 11-61% overall yield. Modification of 8 by bromine substitution at the 5-position of the furan ring, replacement of the secondary amine with an ether bridge, and carboxylation, gave 6-(5-bromofuran-2-yl)-7,9-dimethyl-8,10-dioxo-11-phenyl-7,8,9, 10-tetrahydro-6H-benzo[b]pyrimido [4′,5′:3,4]pyrrolo [1,2-d][1,4]oxazine-2-carboxylic acid 42 (BPO-27), which fully inhibited CFTR with IC50 ～ 8 nM and, compared to 8, had >10-fold greater metabolic stability and much greater polarity/aqueous solubility. In an embryonic kidney culture model of PKD, 42 prevented cyst growth with IC 50 ～ 100 nM. Benzopyrimido-pyrrolo-oxazinediones such as 42 are potential development candidates for antisecretory therapy of PKD.