Abstract
We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC(50)=1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Blood Glucose / metabolism
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Cytochrome P-450 CYP3A / metabolism
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Cytochrome P-450 CYP3A Inhibitors*
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Dipeptidyl Peptidase 4 / metabolism
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Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis
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Dipeptidyl-Peptidase IV Inhibitors / chemistry
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
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Dogs
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Dose-Response Relationship, Drug
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Glucose Tolerance Test
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Haplorhini
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Humans
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Male
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Molecular Conformation
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Rats
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Rats, Zucker
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Stereoisomerism
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Structure-Activity Relationship
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Time Factors
Substances
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2-((6-(3-amino-3-methylpiperidine-1-yl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo(3,2-d)pyrimidine-5-yl)methyl)-4-fluorobenzonitrile
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Blood Glucose
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Cytochrome P-450 CYP3A Inhibitors
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Dipeptidyl-Peptidase IV Inhibitors
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Pyrazoles
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Pyrimidines
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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Dipeptidyl Peptidase 4