Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity

Nihar Kinarivala; Ji Ho Suh; Mina Botros; Paul Webb; Paul C. Trippier

doi:10.1016/j.bmcl.2016.03.028

Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity

Nihar Kinarivala, Ji Ho Suh, Mina Botros, Paul Webb, Paul C. Trippier

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 112nM, 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.

Original language	English (US)
Journal	Bioorganic and Medicinal Chemistry Letters
DOIs	https://doi.org/10.1016/j.bmcl.2016.03.028
State	Accepted/In press - Jan 8 2016

Keywords

BJWXRQUITKSDPA-UHFFFAOYSA-N
KXXHZVHYFQSELL-UHFFFAOYSA-N
Neurodegeneration
Neuroprotection
Pharmacophore identification
PPAR agonist
SEHJHHHUIGULEI-UHFFFAOYSA-N

ASJC Scopus subject areas

Biochemistry
Clinical Biochemistry
Molecular Biology
Molecular Medicine
Organic Chemistry
Drug Discovery
Pharmaceutical Science

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10.1016/j.bmcl.2016.03.028

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title = "Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity",

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 112nM, 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.",

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doi = "10.1016/j.bmcl.2016.03.028",

language = "English (US)",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity

AU - Kinarivala, Nihar

AU - Suh, Ji Ho

AU - Botros, Mina

AU - Webb, Paul

AU - Trippier, Paul C.

PY - 2016/1/8

Y1 - 2016/1/8

N2 - 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 112nM, 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.

AB - 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 112nM, 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.

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KW - KXXHZVHYFQSELL-UHFFFAOYSA-N

KW - Neurodegeneration

KW - Neuroprotection

KW - Pharmacophore identification

KW - PPAR agonist

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Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity

Abstract

Keywords

ASJC Scopus subject areas

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