Abstract
A series of conformationally restricted GPR119 agonists were prepared based around a 3,8-diazabicyclo[3.2.1]octane scaffold. Examples were found to have markedly different pharmacology in mouse and human despite similar levels of binding to the receptor. This highlights the large effects on GPCR phamacology that can result from small structural changes in the ligand, together with inter-species differences between receptors.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Biological Availability
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
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Bridged Bicyclo Compounds, Heterocyclic / chemistry*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Cell Membrane Permeability / drug effects
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Cyclic AMP / metabolism
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Dogs
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Half-Life
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Heterocyclic Compounds, 2-Ring / chemical synthesis
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Heterocyclic Compounds, 2-Ring / chemistry*
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Heterocyclic Compounds, 2-Ring / pharmacokinetics
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Humans
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Madin Darby Canine Kidney Cells
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Mice
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Protein Binding
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / metabolism
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Structure-Activity Relationship
Substances
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Bridged Bicyclo Compounds, Heterocyclic
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GPR119 protein, human
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Heterocyclic Compounds, 2-Ring
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Pyrimidines
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Receptors, G-Protein-Coupled
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Cyclic AMP