TEI-A00114: A new vitamin D3 analogue that inhibits neutrophil recruitment in an acute lung injury hamster model while showing reduced hypercalcemic activity

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 0.4 μg/kg, respectively. TEI-A00114 was also tested by inhaled administration, and its ED40 was calculated as 0.2 μg/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 × 10−9 M, 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.

► TEI-A00114 inhibits neutrophil recruitment in a model of ALI as strong as 1α,25(OH)2D3.
► TEI-A00114’s VDR affinity is 2.5-fold weaker than that of 1α,25(OH)2D3.
► TEI-A00114’s DBP binding affinity is 330.9-fold weaker than that of 1α,25(OH)2D3.
► The calcemic action of TEI-A00114 was 89-fold weaker than that of 1α,25(OH)2D3.