Abstract
Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.
Keywords:
Cannabinoid receptor 2 (CB2); Metabolic stability; Pharmacokinetic properties; Proline; Solubility.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Diabetic Neuropathies / chemically induced
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Diabetic Neuropathies / drug therapy
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Half-Life
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Humans
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Isoxazoles / chemistry*
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Isoxazoles / pharmacokinetics
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Isoxazoles / therapeutic use
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Ligands
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Male
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Microsomes, Liver / metabolism
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Proline / chemistry*
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Proline / pharmacokinetics
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Proline / therapeutic use
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Protein Binding
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Pyrrolidonecarboxylic Acid / analogs & derivatives*
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Pyrrolidonecarboxylic Acid / chemistry
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Pyrrolidonecarboxylic Acid / pharmacokinetics
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Pyrrolidonecarboxylic Acid / therapeutic use
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Rats
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Rats, Wistar
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Receptor, Cannabinoid, CB1 / agonists
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Receptor, Cannabinoid, CB1 / metabolism
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Receptor, Cannabinoid, CB2 / agonists*
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Receptor, Cannabinoid, CB2 / metabolism
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Solubility
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Structure-Activity Relationship
Substances
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Isoxazoles
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Ligands
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2
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Proline
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Pyrrolidonecarboxylic Acid