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α-Lipoic acid-based PPARγ agonists for treating inflammatory skin diseases

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Abstract

Novel thiazolidinedione derivatives of the potent antioxidant, α-lipoic (thioctic, 1,2-dithiolane) acid, were prepared. The prototype N-(2-{4-[2,4-dioxo(1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)-5-(1,2-dithiolan-3-yl)-N-methylpentanamide (designated BP-1003), and dithioester derivatives thereof were shown to be potent activators of peroxisome proliferator-activated receptor gamma (PPARγ) (EC50 range 15–101 nM) and modest activators of PPARα (EC50 5 μM). Both the relatively hydrophobic dithiolane prototype, BP-1003, and its water-soluble dithioglycinate derivative, BP-1017, were shown to inhibit the proliferation of human keratinocytes and suppress the production of interleukin-2 by human peripheral lymphocytes to a greater extent than the antidiabetic thiazolidinedione, rosiglitazone. Both oral and topical administration of BP-1017 showed significant antiinflammatory effects in the oxazolone-sensitized mouse model of allergic contact dermatitis (ACD). These findings suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.

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Abbreviations

ACD:

Allergic contact dermatitis

ATCC:

American Type Culture Collection

FRET:

Fluorescence resonance transactivation

LBD:

Ligand binding domain

LDH:

Lactate dehydrogenase

PBMC:

Peripheral blood mononuclear cells

PHA:

Phytohemagglutinin

PPARγ:

Peroxisome proliferator-activated receptor-gamma

TZD:

Thiazolidinedione

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Acknowledgements

This work was supported by NIH grant 2R42AR44767-02A2 (Bethesda Pharmaceuticals), grants from Bethesda Pharmaceuticals, Inc. (M.V., A.C.), and a Joint Venture grant between Bethesda Pharmaceuticals and the California State University Program for Education and Research in Biotechnology (S.B.).

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Authors and Affiliations

  1. Department Medicinal Chemistry, University of Mississippi, University, MS, USA

    Meenakshi S. Venkatraman, Amar Chittiboyina & Mitchell A. Avery

  2. Novartis Forschungsinstitut GmbH, Vienna, Austria

    Josef Meingassner

  3. Department of Biological Sciences, California State University, 25800 Carlos Bee Blvd, Hayward, CA 94542, USA

    Christopher I. Ho & Stephen C. Benson

  4. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    James Varani

  5. Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA

    Charles N. Ellis

  6. Department of Family Medicine, Kern Medical Center, Bakersfield, CA, USA

    Harrihar A. Pershadsingh

  7. Department of Family Medicine, University of California, Irvine, CA, USA

    Harrihar A. Pershadsingh

  8. Bethesda Pharmaceuticals, Inc, Bakersfield, CA, USA

    Theodore W. Kurtz

  9. Department of Laboratory Medicine, University of California, San Francisco, CA, USA

    Theodore W. Kurtz

Authors
  1. Meenakshi S. Venkatraman
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  2. Amar Chittiboyina
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  3. Josef Meingassner
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  4. Christopher I. Ho
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  5. James Varani
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  6. Charles N. Ellis
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  7. Mitchell A. Avery
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  8. Harrihar A. Pershadsingh
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  9. Theodore W. Kurtz
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  10. Stephen C. Benson
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Corresponding author

Correspondence to Stephen C. Benson.

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Venkatraman, M.S., Chittiboyina, A., Meingassner, J. et al. α-Lipoic acid-based PPARγ agonists for treating inflammatory skin diseases. Arch Dermatol Res 296, 97–104 (2004). https://doi.org/10.1007/s00403-004-0480-5

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  • DOI: https://doi.org/10.1007/s00403-004-0480-5

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