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

• Published in: Bioorganic & medicinal chemistry letters 2007-07, Vol.17 (14), p.3877-3879
• Main Authors: Gao, Ying-Duo, Feng, Dennis, Sheridan, Robert P., Scapin, Giovanna, Patel, Sangita B., Wu, Joseph K., Zhang, Xiaoping, Sinha-Roy, Ranabir, Thornberry, Nancy A., Weber, Ann E., Biftu, Tesfaye
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Dipeptidyl-Peptidase IV Inhibitors; DPP-4; Drug Design; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrolases; Medical sciences; Miscellaneous; Models, Molecular; Molecular modeling; Pharmacology. Drug treatments; Potency; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Pyrimidines - chemistry; Pyrimidines - pharmacology; Quantitative Structure-Activity Relationship; Selectivity against DPP-8/9
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.04.106

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. 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.