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

Ying-Duo Gao; Dennis Feng; Robert P Sheridan; Giovanna Scapin; Sangita B Patel; Joseph K Wu; Xiaoping Zhang; Ranabir Sinha-Roy; Nancy A Thornberry; Ann E Weber; Tesfaye Biftu

doi:10.1016/j.bmcl.2007.04.106

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

Bioorg Med Chem Lett. 2007 Jul 15;17(14):3877-9. doi: 10.1016/j.bmcl.2007.04.106. Epub 2007 May 3.

Authors

Ying-Duo Gao¹, Dennis Feng, Robert P Sheridan, Giovanna Scapin, Sangita B Patel, Joseph K Wu, Xiaoping Zhang, Ranabir Sinha-Roy, Nancy A Thornberry, Ann E Weber, Tesfaye Biftu

Affiliation

¹ Molecular Systems, Merck Research Laboratories, NJ, USA. [email protected]

PMID: 17502141
DOI: 10.1016/j.bmcl.2007.04.106

Abstract

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 DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.

MeSH terms

Dipeptidyl-Peptidase IV Inhibitors*
Drug Design
Models, Molecular
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Quantitative Structure-Activity Relationship

Substances

Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Pyrimidines