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Studies on Pyrrolopyrimidines as Selective Inhibitors of Multidrug-Resistance- Associated Protein in Multidrug Resistance
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Section:Abstract
Multidrug resistance mediated by P-glycoprotein (Pgp) or multidrug-resistance-associated protein (MRP) remains a major obstacle for successful treatment of cancer. Inhibition of Pgp and MRP transport is important for high efficacy of anticancer drugs. While several Pgp inhibitors have entered clinical trials, the development of specific MRP1 inhibitors is still in its infancy. In our screening program, we have identified a pyrrolopyrimidine (4) as a novel and selective MRP1 inhibitor. Subsequent SAR work on the 4-position of the template revealed the phenethylpiperazine side chain as a potent replacement of the benzylthio group of the lead molecule. Introduction of groups at the 2-position seems to have no detrimental effect on activity. Modifications to the nitrile group at the 7-position resulted in the identification of analogues with groups, such as amides, with superior pharmacokinetic profiles. In vivo efficacy has been demonstrated by xenograft studies on selected compounds.
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Renzhong Fu, Xianxiu Xu, Qun Dang, and Xu BaiThe Journal of Organic Chemistry2005 70 (26), 10810-10816Novel tricyclic pyrimido[4,5-b][1,4]benzothiazepines were readily prepared from 5-amino-4,6-bis(arylthio)pyrimidines and carboxylic acids via Bischler−Napieralski-type reactions. The 6-aryl sulfide group of the resulting pyrimido[4,5-b][1,4]...
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- Published In Issue March 11, 2004
- Received August 21, 2003
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