title: TEI-A00114: a new vitamin D3 analogue that inhibits neutrophil recruitment in an acute lung injury hamster model while showing reduced hypercalcemic activity.
abstract: While searching for vitamin D(3) 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)(2)D(3). The estimated effective doses for 40% inhibition (ED(40)) via peroral and intratracheal administration are 7.6 and 0.4 μg/kg, respectively. TEI-A00114 was also tested by inhaled administration, and its ED(40) was calculated as 0.2 μg/kg. The estimated 40% inhibitory concentration (IC(40)) 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)(2)D(3). 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)(2)D(3). 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)(2)D(3) as a candidate for the treatment of acute lung injury.
authors.affiliation: Pharmacological Research Department, Pharmaceuticals Development Research Laboratories, Teijin Institute for Bio-Medical Research, Hino, Tokyo 191-8512, Japan. ya.takano@teijin.co.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuhashi
authors.forename: Seiichi
authors.initials: S
authors.lastname: Ishizuka
authors.forename: Katsushi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Manabu
authors.initials: M
authors.lastname: Chokki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takenouchi
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hazato
authors.forename: Masayasu
authors.initials: M
authors.lastname: Tabe
authors.forename: Minoru
authors.initials: M
authors.lastname: Furuya
authors.forename: Kenji
authors.initials: K
authors.lastname: Manabe
authors.forename: Koichi
authors.initials: K
authors.lastname: Ueno
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D002118:Calcium / Q000097:blood*; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C582316:(2-hydroxy-2-methyl-cyclopentanone-5-ylidene)methyl-9,10-secopregna-5,7,10(19)-triene-1,3-diol; D002762:Cholecalciferol; D002117:Calcitriol; D002118:Calcium