Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors

Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4. (C) 2007 Elsevier Ltd. All rights reserved.