Abstract
Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Chemistry, Pharmaceutical / methods*
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Crystallography, X-Ray / methods
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Cytochrome P-450 CYP3A / chemistry
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Diabetes Mellitus / drug therapy
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Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
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Drug Design
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Molecular Structure
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Piperazine
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Piperazines / chemistry*
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Pyrazines / pharmacology
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Sitagliptin Phosphate
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Structure-Activity Relationship
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Triazoles / pharmacology
Substances
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Dipeptidyl-Peptidase IV Inhibitors
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Piperazines
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Pyrazines
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Triazoles
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Piperazine
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Sitagliptin Phosphate