Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetes
| Autor: | Christopher Higgs, Wiesia Maniara, Neil Victor Harris, Sussie L. Krintel, Kenji Namoto, Alokesh Duttaroy, Finton Sirockin, Christopher A. Hurley, Nils Ostermann, Daniel K. Baeschlin, Robert Edward Mackenzie, Eric Gangl, David E. Clark, Garry Fenton, Jörg Trappe, Amanda Fillmore, Ulrich Hassiepen, Stephen J. Dunsdon, Jon Sutton, Richard Sedrani, Bernd Gerhartz |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Models Molecular animal structures Clinical Biochemistry Pharmaceutical Science Type 2 diabetes Pharmacology Crystallography X-Ray Biochemistry Inhibitory Concentration 50 Structure-Activity Relationship Heterocyclic Compounds Drug Discovery Hydrolase medicine Animals Humans Molecular Biology IC50 Dipeptidyl-Peptidase IV Inhibitors Molecular Structure Chemistry DPP-4 Inhibitors Organic Chemistry medicine.disease Rats Enzyme Activation Diabetes Mellitus Type 2 Molecular Medicine Caco-2 Cells |
| Zdroj: | Bioorganicmedicinal chemistry letters. 22(3) |
| ISSN: | 1464-3405 |
| Popis: | Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50)10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man. |
| Databáze: | OpenAIRE |
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