Synthesis and Anti-inflammatory Properties of 1α,25-Dihydroxy-16-ene-20-cyclopropyl-24-oxo-vitamin D3, a Hypocalcemic, Stable Metabolite of 1α,25-Dihydroxy-16-ene-20-cyclopropyl-vitamin D3

被引：37

作者：

Laverny, Gilles ^{[1
]}

Penna, Giuseppe ^{[1
]}

Uskokovic, Milan ^{[2
]}

Marczak, Stanislaw ^{[2
]}

Maehr, Hubert ^{[2
]}

Jankowski, Pawel ^{[2
]}

Ceailles, Caroline ^{[3
]}

Vouros, Paul ^{[3
]}

Smith, Brenden ^{[4
]}

Robinson, Matthew ^{[4
]}

Reddy, G. Satyanarayana ^{[4
,5
]}

Adorini, Luciano ^{[1
]}

机构：

[1] BioXell, I-20132 Milan, Italy

[2] BioXell Inc, Nutley, NJ 07110 USA

[3] Northeastern Univ, Dept Chem, Barnett Inst, Boston, MA 02115 USA

[4] Epimer LLC, Providence, RI 02906 USA

[5] Brown Univ, Dept Chem, Providence, RI 02912 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 08期

关键词：

VITAMIN-D-RECEPTOR; 1,25-DIHYDROXYVITAMIN D-3; ANALOG; INHIBITION; GROWTH; PARENT; CELLS;

D O I：

10.1021/jm801365a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

1 alpha,25(OH)(2)-16-ene-20-cyclopropyl-vitamin D-3 (13) is several fold more potent than the natural hormone 1 alpha,25-dihydroxyvitamin D-3 (1) as an anti-infilammatory agent. Here, we have further analyzed the anti-inflammatory properties of 13, confirming it as the most potent analogue tested within this family. We then determined the structures of all the natural metabolites of 13, including the 24-oxo metabolite 14, and carried out its synthesis. A comparison of 13 with 14 showed a similar induction of the primary VDR target genes CYP24A1 and CAMP and comparable anti-inflammatory properties as revealed by a similar inhibition of TNF-alpha, IL-12/23p40, IL-6, and IFN-gamma production. Interestingly, 14 displays a 3-fold lower calcemic activity in vivo compared to 13. Collectively, these findings indicate that the strong potency of 13 can be explained by the accumulation of its stable 24-oxo metabolite, which shows immunoregulatory and anti-inflammatory properties superimposable, to those exerted by 13 itself.

引用

页码：2204 / 2213

页数：10