Modulators, CFTR

Mesoionic pyrimido[l,6- ]pyrimidine 94 exhibited platelet aggregation inhibitory activity <2000BMC1917>. 9-Nitro-hexahydropyrimido[l,6- ]pyrimidines of type 222 have arthropodicidal activity <1997WO97/05145>. The zwitterionic pyrimido[l,6- ]pyrimidine-2-carboxylic acid 215 and related compounds are CFTR channel modulators with potential use to treat mucoviscidosis, asthma or diarrhea <2005W02005/039589>. 

Several excellent reviews have appeared recently covering emerging therapies in CF, including CFTR modulators [45-47] and a collection of CFTR modulators are available through the CFF Consortium for research purposes [48]. Multiple structural classes that potentiate CFTR have been identified by screening compound libraries, natural products, and approved drugs. A subset is described below, which has proved amenable to lead optimization. 

Extensive lead optimization around 12 (Vmax = 122 + 9pM/s Kd 0.9 (iM) established that peripheral modifications of the methylbithiazole core modulates corrector activity and resulted in 13 (Vmax = 127 + 8pM/s Kd 0.7 J.M) with improved activity [56], Further studies focused on the bithia-zolyl moiety and concluded that the s-cis conformation of the planar dithia-zole (as shown) is important for F508del-CFTR correction activity [57]. 

Two approaches have been taken to identify CFTR modulators with both CFTR potentiator and CFTR corrector activities in a single molecule. One... 

Cystic fibrosis is a life-threatening genetic disease caused by a dysfunctional cystic fibrosis transmembrane regulator, CFTR protein, which modulates salt and water transport into and out of cells. This ion-channel defect leads to poorly hydrated, thick, mucous secretions in the airways and severely impaired mucociliary func-... 

Phenyl pyrrolo[2,3-b]pyrazine derivatives, previously described as CDK and GSK-3 inhibitors, also potentiate CFTR [46]. The potentiator activity appears to be modulated by substituents in positions 2 and 3 of the ring. At position 2, the best potency was obtained with a 4-hydroxyphenyl group... 

Use of Primary Disease Bronchial Epithelia to Characterize CFTR Modulators... 

Leonhardt, N., Bazin, I., Richaud, P., Marin, E., Vavasseur, A. and Forestier, C., 2001, Antibodies to the CFTR modulate the turgor pressure of guard cell protoplasts via slow anion channels. FEBSLett. 494 15-18. 

Small molecule modulators of CFTR function may be useful in the treatment of cystic fibrosis, secretory diarrhea and polycystic kidney disease. The most common mutation in the CFTR gene, F508 deletion (AF508), causes retention of F508-CFTR in the endoplasmic reticulum and... 

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