931706-15-9

Usage

Uses

Used in Cystic Fibrosis Treatment:
PPQ-102 is used as a therapeutic agent for the treatment of cystic fibrosis, a genetic disorder characterized by the production of abnormally thick mucus. At a concentration of 5 μM, PPQ-102 has been shown to completely prevent Sp-8-Br-cAMP-induced cyst formation and reduce the size of preformed cysts in an ex vivo murine neonatal kidney organ culture. This suggests its potential in managing the symptoms and progression of cystic fibrosis by targeting the underlying chloride transport defects.
Used in Pharmaceutical Research:
PPQ-102 is also used as a research tool in the development and study of drugs targeting CFTR channels. Its ability to inhibit CFTR-mediated chloride current makes it a valuable compound for investigating the mechanisms of CFTR regulation and the development of new therapeutic strategies for cystic fibrosis and other related chloride channelopathies.
Used in Drug Delivery Systems:
PPQ-102 can be incorporated into drug delivery systems to improve its bioavailability, targeting, and therapeutic efficacy. By employing various carriers such as nanoparticles or other advanced delivery platforms, PPQ-102 can be more effectively delivered to the target cells and tissues, enhancing its potential as a treatment for cystic fibrosis and other related conditions.

Upstream product

• 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 
• 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 

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 academic research and scientific papers

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.

Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model

Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of ～110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347 analogues established structure-activity relationships. 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 IC50 ～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. 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. 2009 American Chemical Society.