Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV
| Autor: | Kenji Namoto, François Gessier, Garry Fenton, Mandy Beswick, Finton Sirockin, Alokesh Duttaroy, Suzie Ferreira, Ulrich Hassiepen, Stefanie Flohr, Bernd Gerhartz, Jörg Trappe, Jon Sutton, Nils Ostermann, David E. Clark, Daniel K. Baeschlin, Richard Sedrani |
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| Rok vydání: | 2013 |
| Předmět: |
animal structures
Pyrrolidines Dipeptidyl Peptidase 4 Clinical Biochemistry Pharmaceutical Science Administration Oral Adamantane Pharmacology Crystallography X-Ray Biochemistry Dipeptidyl peptidase chemistry.chemical_compound Inhibitory Concentration 50 Methylamines Pharmacokinetics Drug Discovery Nitriles Animals Humans Molecular Biology Vildagliptin Dipeptidyl-Peptidase IV Inhibitors Molecular Structure Chemistry Aryl Organic Chemistry Sitagliptin Phosphate Triazoles Rats Enzyme Activation Cyclization Pyrazines Molecular Medicine Caco-2 Cells |
| Zdroj: | Bioorganicmedicinal chemistry letters. 24(3) |
| ISSN: | 1464-3405 |
| Popis: | The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat. |
| Databáze: | OpenAIRE |
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