Abstract
We report the pharmacophore of the peroxisome proliferator-activated receptor δ (PPARδ) agonist natural product phosphoiodyn A is the phosphonate core. Synthesis of simplified phosphonate esters 13 and 15 provide structurally novel, highly selective and potent PPARδ agonists (EC50=78 and 112 nM, respectively). Further, both compounds demonstrate significant neuroprotective activity in an in vitro cellular model indicating that phosphonates may be an effective novel scaffold for the design of therapeutics for the treatment of neurodegenerative disorders.
Keywords:
Neurodegeneration; Neuroprotection; PPAR agonist; Pharmacophore identification.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Dose-Response Relationship, Drug
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Humans
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Hydrocarbons, Iodinated / chemical synthesis
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Hydrocarbons, Iodinated / chemistry
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Hydrocarbons, Iodinated / pharmacology*
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Molecular Structure
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Neurodegenerative Diseases / drug therapy*
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Organophosphorus Compounds / chemical synthesis
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Organophosphorus Compounds / chemistry
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Organophosphorus Compounds / pharmacology*
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PPAR delta / agonists*
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PPAR-beta / agonists*
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Polyynes / chemical synthesis
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Polyynes / chemistry
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Polyynes / pharmacology*
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Structure-Activity Relationship
Substances
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Hydrocarbons, Iodinated
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Neuroprotective Agents
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Organophosphorus Compounds
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PPAR delta
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PPAR-beta
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phosphoiodyn A
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Polyynes