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Archives of Dermatological Research

, Volume 296, Issue 3, pp 97–104 | Cite as

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

  • Meenakshi S. Venkatraman
  • Amar Chittiboyina
  • Josef Meingassner
  • Christopher I. Ho
  • James Varani
  • Charles N. Ellis
  • Mitchell A. Avery
  • Harrihar A. Pershadsingh
  • Theodore W. Kurtz
  • Stephen C. Benson
Original Paper

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.

Keywords

Thiazolidinedione Peroxisome proliferator-activated receptor-γ α-Lipoic acid Inflammation Dermatitis Psoriasis 

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

Notes

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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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Meenakshi S. Venkatraman
    • 1
  • Amar Chittiboyina
    • 1
  • Josef Meingassner
    • 2
  • Christopher I. Ho
    • 3
  • James Varani
    • 4
  • Charles N. Ellis
    • 5
  • Mitchell A. Avery
    • 1
  • Harrihar A. Pershadsingh
    • 6
    • 7
  • Theodore W. Kurtz
    • 8
    • 9
  • Stephen C. Benson
    • 3
  1. 1.Department Medicinal ChemistryUniversity of MississippiUniversityUSA
  2. 2.Novartis Forschungsinstitut GmbHViennaAustria
  3. 3.Department of Biological SciencesCalifornia State UniversityHaywardUSA
  4. 4.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA
  5. 5.Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborUSA
  6. 6.Department of Family MedicineKern Medical CenterBakersfieldUSA
  7. 7.Department of Family MedicineUniversity of CaliforniaIrvineUSA
  8. 8.Bethesda Pharmaceuticals, IncBakersfieldUSA
  9. 9.Department of Laboratory MedicineUniversity of CaliforniaSan FranciscoUSA

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