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Eur J Med Chem. 2012 Jun;52:205-12. doi: 10.1016/j.ejmech.2012.03.015. Epub 2012 Mar 17.

Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization.

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Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kai Yuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.


We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development.

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