Analogs of 1alpha,25-dihydroxyvitamin D3 with high potency in induction of osteoclastogenesis and prevention of dendritic cell differentiation: synthesis and biological evaluation of 2-substituted 19-norvitamin D analogs

Bioorganic & Medicinal Chemistry
Mika ShimazakiMasato Shimizu

Abstract

In our previous papers, we found that introduction of a substituent at C(2) into 1alpha,25-dihydroxy-19-norvitamin D(3) (2a) caused dramatic changes in binding affinity for the vitamin D receptor (VDR) and in transcriptional activity compared with the parent compound. To investigate the broad biological activity of 2-substituted 19-norvitamin D analogs, we synthesized two new (20S)-2-hydroxyethylidene-19-norvitamin D derivatives (3b and 4b) and a total of 16 A-ring-modified analogs including 3b and 4b were tested for the following in vitro and in vivo biological activities: (1) affinity for the VDR, (2) transcriptional activity, (3) osteoclast formation, (4) bone calcium mobilization in rats, and (5) effects on differentiation of dendritic cells (DCs). The biological effects of the analogs were compared with those of 1alpha,25-dihydroxyvitamin D(3) (1a) and 2MD, which is being developed for the treatment of osteoporosis. The efficacy of the (20S)-19-norvitamin D analogs with 2-hydroxyethylidene, 2-hydroxyethoxy, and 2-methyl moieties (3b, 5b, 6b, and 9b) was more than 10-fold stronger than that of 1a with respect to transcriptional activity, ability to induce osteoclast formation, and ability to inhibit CD86 expression, a marke...Continue Reading

References

Oct 15, 1973·Experientia·E Havinga
Sep 1, 1995·American Journal of Hypertension·L LindS Ljunghall
Nov 22, 1997·Hypertension·E Kristal-BonehJ Ribak
Sep 1, 1993·The Journal of Steroid Biochemistry and Molecular Biology·I S MathiasenL Binderup
May 10, 2001·Proceedings of the National Academy of Sciences of the United States of America·G Tocchini-ValentiniD Moras
Dec 26, 2001·Clinica Chimica Acta; International Journal of Clinical Chemistry·K KawanaK Kushida
Oct 11, 2002·Proceedings of the National Academy of Sciences of the United States of America·Nirupama K ShevdeHector F DeLuca
Oct 26, 2002·Endocrinology·Vijaya VegesnaH Phillip Koeffler
May 16, 2003·Nature·William J BoyleDavid L Lacey
Jul 1, 2004·The Journal of Steroid Biochemistry and Molecular Biology·Agnieszka GlebockaHector F DeLuca
Jul 1, 2004·The Journal of Steroid Biochemistry and Molecular Biology·Hector F DeLuca
Jul 1, 2004·The Journal of Steroid Biochemistry and Molecular Biology·Toshie FujishimaHiroaki Takayama
Jul 1, 2004·The Journal of Steroid Biochemistry and Molecular Biology·Luciano AdoriniMilan Uskokovic
Feb 17, 2005·Bioorganic & Medicinal Chemistry Letters·Masato ShimizuSachiko Yamada

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Citations

Jul 8, 2008·Molecular Aspects of Medicine·Paul H Anderson, Gerald J Atkins
Jul 25, 2009·American Journal of Physiology. Renal Physiology·José M ValdivielsoElvira Fernández
Jun 22, 2013·ChemMedChem·Can-Fei ZhangZhao-Peng Liu
Jul 28, 2020·Pharmaceuticals·Susana Fernández, Miguel Ferrero

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