Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit
Autor: | Kenton L. Longenecker, Bradley J. Backes, David W A Beno, James M. Trevillyan, Hing L. Sham, Hana Kopecka, Michael A. Stashko, Gregory Hamilton, Zhonghua Pei, David Madar, Stephen J. Ballaron, Bradley A. Zinker, Candace Black-Schaefer, Thomas H. Lubben, Chunqiu Lai, Thomas W. von Geldern, Anita J Kempf-Grote, Kent D. Stewart, Zhenping Tian, Amanda K Mika |
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Rok vydání: | 2006 |
Předmět: |
Blood Glucose
Pyrrolidines Stereochemistry Chemistry Pharmaceutical Clinical Biochemistry Molecular Conformation Pharmaceutical Science Phenethylamines Pharmacology Biochemistry Dipeptidyl peptidase Pyrrolidine chemistry.chemical_compound Pharmacokinetics In vivo Drug Discovery Cyclohexenes Potency Animals Hypoglycemic Agents Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Dipeptidyl-Peptidase IV Inhibitors biology Chemistry Organic Chemistry Rats Enzyme Diabetes Mellitus Type 2 Models Chemical Enzyme inhibitor Drug Design biology.protein Molecular Medicine Female |
Zdroj: | Bioorganicmedicinal chemistry letters. 17(7) |
ISSN: | 0960-894X |
Popis: | A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal. |
Databáze: | OpenAIRE |
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