PMID- 26232635
OWN - NLM
STAT- MEDLINE
DCOM- 20170704
LR  - 20171207
IS  - 1879-1220 (Electronic)
IS  - 0960-0760 (Linking)
VI  - 164
DP  - 2016 Nov
TI  - Synthesis, metabolism, and biological activity of 
      2-[3-(tetrazolyl)propyl]-1alpha,25-dihydroxy-19-norvitamin D(3).
PG  - 40-44
LID - S0960-0760(15)30029-7 [pii]
LID - 10.1016/j.jsbmb.2015.07.016 [doi]
AB  - Recently, we found that 2alpha-[2-(tetrazol-2-yl)ethyl]-1alpha,25-dihydroxyvitamin D(3) 
      showed higher osteocalcin promoter transactivation activity in human osteosarcoma 
      (HOS) cells and a greater therapeutic effect in ovariectomized (OVX) rats in vivo 
      than those of active vitamin D(3), 1alpha,25(OH)(2)D(3). We were interested in 
      introducing a heterocyclic ring to the C2 position of the seco-steroidal 
      structure via an alkyl linker, and four novel C2-(3-tetrazolylpropyl) substituted 
      1alpha,25-dihydroxy-19-norvitamin D(3) analogs, 2alpha-[3-(tetrazol-1-yl)propyl]-, 
      2beta-[3-(tetrazol-1-yl)propyl]-, 2alpha-[3-(tetrazol-2-yl)propyl]-, and 
      2beta-[3-(tetrazol-2-yl)propyl]-19-nor-1alpha,25(OH)(2)D(3) were synthesized. Among 
      them, 2alpha-[3-(tetrazol-1-yl)propyl]-19-nor-1alpha,25(OH)(2)D(3) showed weak binding 
      affinity for human vitamin D receptor (hVDR) (2.6% of 1alpha,25(OH)(2)D(3) and ca. 
      15% of 19-nor-1alpha,25(OH)(2)D(3)) and weak VDR transactivation activity in HOS 
      cells (EC(50) 7.3nM, when 1alpha,25(OH)(2)D(3)0.23nM). Although the other three 
      compounds could not act as VDR binders by evaluation of the competition assays, 
      2alpha-[3-(tetrazol-2-yl)propyl]-19-nor-1alpha,25(OH)(2)D(3) showed weak transactivation 
      activity (EC(50) 12.5nM). Metabolic stability of the 2alpha-substituted compounds 
      2alpha-[3-(tetrazol-1-yl)propyl]- and 
      2alpha-[3-(tetrazol-2-yl)propyl]-19-nor-1alpha,25(OH)(2)D(3) was higher than that of the 
      2beta-substituted counterparts 2beta-[3-(tetrazol-1-yl)propyl]- and 
      2beta-[3-(tetrazol-2-yl)propyl]-19-nor-1alpha,25(OH)(2)D(3) against human CYP24A1. 
      Introduction of a tetrazole ring to the C2-position of the 19-norvitamin D(3) 
      skeleton with the propyl linker led to weak VDR agonistic activity with stability 
      against CYP24A1 metabolism.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Takano, Masashi
AU  - Takano M
AD  - Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, 
      Tokyo 173-8605, Japan.
FAU - Yasuda, Kaori
AU  - Yasuda K
AD  - Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, 
      Japan.
FAU - Higuchi, Erika
AU  - Higuchi E
AD  - Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, 
      Tokyo 173-8605, Japan.
FAU - Tohyama, Eri
AU  - Tohyama E
AD  - Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, 
      Japan.
FAU - Takeuchi, Akiko
AU  - Takeuchi A
AD  - Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., Hino, Tokyo 
      191-8512, Japan.
FAU - Sakaki, Toshiyuki
AU  - Sakaki T
AD  - Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, 
      Japan.
FAU - Kittaka, Atsushi
AU  - Kittaka A
AD  - Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, 
      Tokyo 173-8605, Japan. Electronic address: akittaka@pharm.teikyo-u.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150729
PL  - England
TA  - J Steroid Biochem Mol Biol
JT  - The Journal of steroid biochemistry and molecular biology
JID - 9015483
RN  - 0 (1-hydroxy-19-norvitamin D3)
RN  - 0 (2-(3-(tetrazolyl)propyl)-1,25-dihydroxy-19-norvitamin D3)
RN  - 0 (Ethylenes)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tetrazoles)
RN  - 0 (VDR protein, human)
RN  - 104982-03-8 (Osteocalcin)
RN  - 91GW059KN7 (ethylene)
RN  - EC 1.14.15.16 (CYP24A1 protein, human)
RN  - EC 1.14.15.16 (Vitamin D3 24-Hydroxylase)
RN  - FXC9231JVH (Calcitriol)
SB  - IM
MH  - Animals
MH  - Calcitriol/*analogs & derivatives/chemical synthesis/chemistry
MH  - Chromatography, High Pressure Liquid
MH  - Drug Design
MH  - Ethylenes/chemistry
MH  - Humans
MH  - Osteocalcin/genetics
MH  - Osteoporosis/drug therapy
MH  - Osteosarcoma/*metabolism
MH  - Ovariectomy
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - Receptors, Calcitriol/genetics
MH  - Recombinant Proteins/chemistry
MH  - Tetrazoles/*chemical synthesis/chemistry
MH  - Transcriptional Activation
MH  - Vitamin D3 24-Hydroxylase/genetics
OTO - NOTNLM
OT  - 19-Norvitamin D(3) analog
OT  - CYP24A1
OT  - Metabolism
OT  - Synthesis
OT  - Transactivation
OT  - Vitamin D receptor
EDAT- 2015/08/02 06:00
MHDA- 2017/07/05 06:00
CRDT- 2015/08/02 06:00
PHST- 2015/06/02 00:00 [received]
PHST- 2015/07/22 00:00 [revised]
PHST- 2015/07/27 00:00 [accepted]
PHST- 2015/08/02 06:00 [pubmed]
PHST- 2017/07/05 06:00 [medline]
PHST- 2015/08/02 06:00 [entrez]
AID - S0960-0760(15)30029-7 [pii]
AID - 10.1016/j.jsbmb.2015.07.016 [doi]
PST - ppublish
SO  - J Steroid Biochem Mol Biol. 2016 Nov;164:40-44. doi: 10.1016/j.jsbmb.2015.07.016. 
      Epub 2015 Jul 29.