BP-1107 [{2-[4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-phenoxy]-ethyl}-methyl-amide]: A Novel Synthetic Thiazolidinedione That Inhibits Epidermal Hyperplasia in Psoriatic Skin-Severe-Combined Immunodeficient Mouse Transplants after Topical Application

Abstract

Recent studies have demonstrated that orally administered thiazolidinedione ligands of the peroxisome proliferator-activated receptor-␥ 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, thiazoladinedione derivative, BP-1107 ({2-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-ethyl}-methyl-amide), 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 with 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 antipsoriatic therapy may be provided with this agent.Psoriasis is an inflammatory skin disease characterized by excessive keratinocyte proliferation, leading to a significant thickening of the epidermis, expansion of epidermal rete pegs into papillary dermal space, and continuous shedding of the thickened epidermis. The etiology of the disease is complex and not well understood. T cells are almost certainly involved in the initiation of psoriatic lesions. Activated T cells in the region of the dermal-epidermal junction are thought to drive the hyperplastic proliferative response through elaboration of Th1 cytokines, including tumor necrosis factor-␣, interferon-␥, and various interleukins (IL-2, IL-6, and IL-8) (Nickoloff, 1991;Valdimarsson et al., 1995;Austin et al., 1999). Although the immune system is likely to be responsible for initiating the disease, the subsequent hyperproliferative response in the keratinocytes seems to be a direct consequence of proproliferative intraepidermal events.In recent studies, we (Ellis et al

Preclinical Studies of a Specific PPARγ Modulator in the Control of Skin Inflammation

“…In mouse models of hyperproliferative and inflammatory skin diseases, topical application of PPARg ligands reduces epidermal hyperplasia, normalizes keratinocytes differentiation (Mao- Qiang et al, 2004;Bhagavathula et al, 2005;Demerjian et al, 2006), and improves permeability barrier homeostasis without affecting normal skin (Man et al, 2006). Moreover, the inflammation mediated by T helper type 1 cell (Th1)-related cytokines is significantly reduced (Hatano et al, 2010).…”

The Role of Transcription Factor PPAR-γ in the Pathogenesis of Psoriasis, Skin Cells, and Immune Cells

“…It also reduces the inflammatory response and improves the functioning of the skin barrier. Treatment of animals and cultured cells with agonists of PPAR-γ (troglitazone, rosiglitazone, pioglitazone, and BP-1107) decreases the proliferation rate of epidermal keratinocytes [ 108 , 115 , 116 ]. The antiproliferative effect is fully reversible and removes the used TZD from the culture medium [ 115 , 116 ].…”

Statistical evaluation and experimental design of a psoriasis xenograft transplantation model treated with cyclosporin A

“…During the last decade, several studies employing both aspects of the model, have aimed to evaluate the effect of different anti‐psoriatic drugs (Tables S1 and S2) (9–35). Well‐known and clinically established anti‐psoriatic therapeutics confirmed the validity and the predictivity of the model (10–15,17–19,21,22,25–32,34,35), prompting its use for new and unknown drugs.…”