4-Arylcyclohexylalanine analogs as potent, selective, and orally active inhibitors of dipeptidyl peptidase IV

A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC 50 = 4.8 nM), which showed an excellent pharmacokinetic prof...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-11, Vol.17 (21), p.5806-5811
Hauptverfasser:	Kaelin, David E., Smenton, Abigail L., Eiermann, George J., He, Huaibing, Leiting, Barbara, Lyons, Kathryn A., Patel, Reshma A., Patel, Sangita B., Petrov, Alexsandr, Scapin, Giovanna, Wu, Joseph K., Thornberry, Nancy A., Weber, Ann E., Duffy, Joseph L.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Alanine - analogs & derivatives Alanine - chemistry Alanine - pharmacology Animals Area Under Curve Biological and medical sciences Dipeptidyl-Peptidase IV Inhibitors DPP-4 inhibitors General and cellular metabolism. Vitamins Medical sciences Mice Models, Molecular Pharmacology. Drug treatments Protease Inhibitors - administration & dosage Protease Inhibitors - chemistry Protease Inhibitors - pharmacokinetics Protease Inhibitors - pharmacology
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Beschreibung
Zusammenfassung:	A novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC 50 = 4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2007.08.049