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TEI-A00114: A new vitamin D3analogue that inhibits neutrophil recruitment in an acute lung injury hamster model while showing reduced hypercalcemic activity

Authors
Journal
Steroids
0039-128X
Publisher
Elsevier
Volume
77
Issue
14
Identifiers
DOI: 10.1016/j.steroids.2012.09.008
Keywords
  • Acute Lung Injury
  • Neutrophils
  • Vitamin D3Analogues
  • Tei-A00114
  • Calcemic Action
  • Il-8
Disciplines
  • Biology

Abstract

Abstract While searching for vitamin D3 analogues which inhibit neutrophil recruitment in the lung without elevating plasma calcium level, we found that (5Z,7E)-(1S,3R)-20(R)-[(5E)-(2S)-2-hydroxy-2-methyl-cyclopentanone-5-ylidene]methyl-9,10-secopregna-5,7,10(19)-triene-1,3-diol (TEI-A00114) had the best efficacy and calcemic action. TEI-A00114 has a vitamin D receptor affinity 2.5-fold weaker and a vitamin D binding protein affinity 330.9-fold weaker than those of 1α,25(OH)2D3. The estimated effective doses for 40% inhibition (ED40) via peroral and intratracheal administration are 7.6 and 0.4μg/kg, respectively. TEI-A00114 was also tested by inhaled administration, and its ED40 was calculated as 0.2μg/kg. The estimated 40% inhibitory concentration (IC40) of TEI-A00114 on interleukin (IL)-8 production induced by lipopolysaccharide and on IL-1β in human whole blood cells in vitro were 9.8×10−8 or 1.8×10−9M, respectively. These levels of TEI-A00114’s activities are equal to those of 1α,25(OH)2D3. On the other hand, the calcemic action of TEI-A00114, which was evaluated at day 14 after sequential peroral quaque die administration, was 89-fold weaker (molar ratio) than that of 1α,25(OH)2D3. These results indicate that TEI-A00114 has a dissociated profile between inhibition of neutrophil recruitment in the lung and calcemic action, suggesting its suitability over 1α,25(OH)2D3 as a candidate for the treatment of acute lung injury.

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