Marked Suppression of T Cells by a Benzothiophene Derivative in Patients with Human T-Lymphotropic Virus Type I-Associated Myelopathy/Tropical Spastic Paraparesis

Article

Author: Izumo, Shuji ; Makino, Masahiko ; Yokoyama, Mitchel M. ; Wakamatsu, Shin-Ichi ; Baba, Masanori ; Suruga, Yukio ; Azuma, Miyuki

ABSTRACTIn a search for new anti-autoimmune agents that selectively suppress activation of autoreactive T cells, one such agent, 5-methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide (CI-959-A), was found to be effective. This compound, which is known to suppress tumor necrosis factor alpha (TNF-α)-induced CD54 expression, inhibited the primary proliferative response of the T cell to antigen (Ag)-presenting cells (APCs) including allogenic dendritic cells (DCs), autologous Epstein-Barr virus-infected B cells, and human T lymphotropic virus type I (HTLV-I)-infected T cells. Autoreactive T cells from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) spontaneously proliferate in vitro, and their activation is reported to be associated with CD54 expression. The spontaneous proliferation of T cells from patients with HAM/TSP was entirely blocked by CI-959-A. However, in this study, the T-cell proliferation in 15 patients with HAM/TSP was found to depend more extensively on major histocompatibility complex (MHC) class II and CD86 than on CD54 Ags. Since most important APCs for the development of HAM/TSP are DCs and HTLV-I-infected T cells, the effect of CI-959-A on DC generation and on the expression of surface molecules on activated T cells is examined. CI-959-A suppressed recombinant granulocyte-macrophage colony stimulating factor (GM-CSF)- and recombinant interleukin-4-dependent differentiation of DCs from monocytes and inhibited the expression of CD54 and, more extensively, MHC class II and CD86 Ags. CI-959-A showed little toxicity toward lymphoma or HTLV-I-infected T-cell lines or toward monocytes and cultured DCs. These results suggest that CI-959-A might be a potent anti-HAM/TSP agent.

01 Nov 1998·Toxicologic PathologyQ4 · MEDICINE

Nasal Toxicity of CI-959, A Novel Anti-inflammatory Drug, in Wistar Rats and Beagle Dogs

Q4 · MEDICINE

Article

Author: Walsh, Kathleen M. ; Courtney, Cynthia L.

CI-959, 5-methoxy-3-(1-methylethoxy)- N-1H-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide, an anti-inflammatory agent, was considered for development as a treatment for rhinitis. Two-week topical nasal studies in Wistar rats and Beagle dogs were performed to assess nasal toxicity of CI-959. Rats were given daily doses in the right nostril of 0.05 ml of solutions of varying concentrations (0.5, 2, 10, 20, 30, 60, and 90 mg/ml; doses of 0.08, 0.3, 1.6, 3.2, 4.8, 9.6, and 14.6 mg/kg) of CI-959. Beagle dogs were given daily doses in the right nostril of 0.5 ml of 10, 20, 30, 60, and 90 mg/ml solutions (doses of 0.5, 0.8, 1.2, 2.8, and 3.7 mg/kg) of CI-959. Rats given ≥60 mg/ml either lost weight or had decreased weight gain. Salivation at dosing was seen in both species. Four sections of nasal cavity were examined from each animal. In rats, 0.5 mg/ml was the "no effect" dose; minimal changes were seen at 2 mg/ ml, and significant changes were dose related in severity at ≥10 mg/ml in all 4 nasal levels. Degeneration and necrosis of respiratory and olfactory epithelia were minimal to moderate in severity. Adhesions and fibro-osseous proliferation of ethmoturbinates, epithelial hyperplasia, squamous metaplasia, and exudate were also seen. In dogs, 10 mg/ml was the no effect dose; respiratory epithelium was affected at ≥20 mg/ml. Respiratory epithelial degeneration was minimal to mild, with loss of ciliated and goblet cells and thinning of mucosa. Distribution of degeneration increased with increased concentrations. In both species, in accordance with the suggested action of CI-959, infiltration with neutrophils was not significant. CI-959 was locally toxic to nasal cavity respiratory and olfactory epithelia in rats and respiratory epithelium in dogs.

01 Jun 1997·Life SciencesQ3 · MEDICINE

Suppression of polarity, locomotion and F-actin levels of Walker carcinosarcoma cells by the inhibitor CI-959

Q3 · MEDICINE

Article

Author: Hansuli Keller ; Nicole Von Tscharner Biino ; Hartmut Porzig

Locomotor activity of tumor cells is an important factor for the capacity for invasion and metastasis. Therefore, inhibitors interfering with cellular mechanisms regulating spontaneous cell locomotion are of particular interest for cancer therapy. CI-959, a new benzothiophene cell activation inhibitor, has the capacity to suppress spontaneous polarity and locomotion of Walker carcinosarcoma cells. Suppression of polarity and locomotion was closely associated with a reduction in the relative amount of F-actin. The mechanisms involved in suppression of motility are Ca2(+)-independent and not related to cell-substratum adhesion. Walker carcinosarcoma cells appear to be able to locomote at very low (nM) levels of free [Ca2+]i.

100 Deals associated with CI-959

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	US	-	-
Asthma	Phase 2	-	Pfizer Inc.	-
Colitis, Ulcerative	Phase 2	US	-	-
Crohn Disease	Phase 2	US	-	-
Myocardial Ischemia	Phase 2	-	Pfizer Inc.	-
Myocardial Ischemia	Phase 2	US	-	-
Neoplasms	Phase 2	CH	-	-
Peptic Ulcer	Phase 2	US	-	-
Rhinitis, Allergic	Phase 2	-	Pfizer Inc.	-
Rhinitis, Allergic	Phase 2	US	-	-

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