Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor

Takeru Kudo, Michiyasu Ishizawa, Kazuki Maekawa, Makoto Nakabayashi, Yusuke Watarai, Hikaru Uchida, Hiroaki Tokiwa, Teikichi Ikura, Nobutoshi Ito, Makoto Makishima, Sachiko Yamada

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue-selective VDR modulators, we have designed vitamin D analogues with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26-adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivatives (ADTK1-4, 4b,a and 5a,b). These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10-9-10-8 M with 40-80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure-activity relationships of these compounds on the basis of their X-ray crystal structures.

Original languageEnglish
Pages (from-to)4073-4087
Number of pages15
JournalJournal of Medicinal Chemistry
Volume57
Issue number10
DOIs
Publication statusPublished - May 22 2014
Externally publishedYes

Fingerprint

Adamantane
Calcitriol Receptors
Vitamin D
Ligands
Secondary Hyperparathyroidism
Hypercalcemia
Structure-Activity Relationship
Psoriasis
Transcriptional Activation
Autoimmune Diseases
Osteoporosis
Cardiovascular Diseases
X-Rays
Gene Expression
Therapeutics
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Kudo, T., Ishizawa, M., Maekawa, K., Nakabayashi, M., Watarai, Y., Uchida, H., ... Yamada, S. (2014). Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor. Journal of Medicinal Chemistry, 57(10), 4073-4087. https://doi.org/10.1021/jm401989c

Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor. / Kudo, Takeru; Ishizawa, Michiyasu; Maekawa, Kazuki; Nakabayashi, Makoto; Watarai, Yusuke; Uchida, Hikaru; Tokiwa, Hiroaki; Ikura, Teikichi; Ito, Nobutoshi; Makishima, Makoto; Yamada, Sachiko.

In: Journal of Medicinal Chemistry, Vol. 57, No. 10, 22.05.2014, p. 4073-4087.

Research output: Contribution to journalArticle

Kudo, T, Ishizawa, M, Maekawa, K, Nakabayashi, M, Watarai, Y, Uchida, H, Tokiwa, H, Ikura, T, Ito, N, Makishima, M & Yamada, S 2014, 'Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor', Journal of Medicinal Chemistry, vol. 57, no. 10, pp. 4073-4087. https://doi.org/10.1021/jm401989c
Kudo, Takeru ; Ishizawa, Michiyasu ; Maekawa, Kazuki ; Nakabayashi, Makoto ; Watarai, Yusuke ; Uchida, Hikaru ; Tokiwa, Hiroaki ; Ikura, Teikichi ; Ito, Nobutoshi ; Makishima, Makoto ; Yamada, Sachiko. / Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 10. pp. 4073-4087.
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