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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 18, 2005; DOI: 10.1124/jpet.105.091066

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Received for publication June 17, 2005.
Revised August 17, 2005.
Accepted for publication August 17, 2005.

BP-1107: A Novel, Synthetic Thiazolidinedione that inhibits epidermal hyperplasia in Psoriatic skin - SCID Mouse transplants following topical application

Narasimharao Bhagavathula 1, Kamalakar C Nerusu 2, Mahendranath Reddy 3, Charles N Ellis 4, Amar Chittiboyina 5, Mitchell Avery 5, Harrihar A Pershadsingh 6, Theodore W Kurtz 7, James Varani 2*

1 University of Michigan 2 Dept. of Pathology, University of Michigan, Ann Arbor, MI 3 Dept. of Pathology, University of Michigan 4 Dept. of Dermatology, University of Michigan, Ann Arbor, MI 5 Dept. of Medicinal Chemistry, University of Mississippi, Oxford, MS 6 Dept. of Family Medicine, Kern Medical Center, University of California, Irvine, CA 7 Dept. of Laboratory Medicine, University of California, San Francisco, CA

* Address correspondence to: E-mail: varani{at}umich.edu

Abstract

Recent studies have demonstrated that orally administered thiazolidinedione ligands of the peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) can ameliorate clinical features of psoriasis in humans. Thiazolidinediones also inhibit the proliferation of psoriatic keratinocytes in monolayer and organ culture, and at least one of these agents (troglitazone) inhibits epidermal hyperplasia of human psoriatic skin transplanted to severe combined immunodeficient (scid) mice. In the present study we show that a novel, synthetic, thiazolidinedione derivative (BP-1107) is capable of inhibiting psoriatic hyperplasia in the scid mouse transplant model after topical application. Like other thiazolidinediones, BP-1107 inhibits proliferation of rapidly growing keratinocytes in monolayer culture, but compared to these agents, the effective dose of BP-1107 needed to suppress keratinocyte proliferation is much lower. Concentrations of BP-1107 that effectively inhibit keratinocyte function have no detrimental effect on dermal fibroblasts. These data suggest that effective topical anti-psoriatic therapy may be provided with this agent.


Key words: PPAR-gamma, Thiazolidinedione, fibroblast, keratinocytes, psoriasis, skin transplant


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N. Bhagavathula, K. C. Nerusu, A. Hanosh, M. N. Aslam, T. B. Sundberg, A. W. Opipari Jr., K. Johnson, S. Kang, G. D. Glick, and J. Varani
7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(naphthalen-2-ylmethyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (Bz-423), a Benzodiazepine, Suppresses Keratinocyte Proliferation and Has Antipsoriatic Activity in the Human Skin-Severe, Combined Immunodeficient Mouse Transplant Model
J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 938 - 947.
[Abstract] [Full Text] [PDF]


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