| Literature DB >> 22177783 |
Jon M Sutton1, David E Clark, Stephen J Dunsdon, Garry Fenton, Amanda Fillmore, Neil V Harris, Chris Higgs, Chris A Hurley, Sussie L Krintel, Robert E MacKenzie, Alokesh Duttaroy, Eric Gangl, Wiesia Maniara, Richard Sedrani, Kenji Namoto, Nils Ostermann, Bernd Gerhartz, Finton Sirockin, Jörg Trappe, Ulrich Hassiepen, Daniel K Baeschlin.
Abstract
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. CrownEntities:
Mesh：
Substances：
Year: 2011 PMID： 22177783 DOI： 10.1016/j.bmcl.2011.11.054
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823