Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia

Abstract Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that...

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Autores principales:	Santosh A. Khedkar, Mohammed A. Samad, Sangita Choudhury, Ji Yoo Lee, Dongsheng Zhang, Ravi I. Thadhani, S. Ananth Karumanchi, Alan C. Rigby, Peter M. Kang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/853bea727f7e4295a02ec950760e473a
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spelling	oai:doaj.org-article:853bea727f7e4295a02ec950760e473a2021-12-02T16:08:23ZIdentification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia10.1038/s41598-017-08670-y2045-2322https://doaj.org/article/853bea727f7e4295a02ec950760e473a2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08670-yhttps://doaj.org/toc/2045-2322Abstract Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that activate the vitamin D receptor (VDR), but are devoid of hypercalcemia. A lead compound (known as VDR 4-1) demonstrated potent transcriptional activities in a VDR reporter gene assay, and significantly ameliorated cardiac hypertrophy in cell culture studies and in animal models. VDR 4-1 also effectively suppressed secondary hyperparathyroidism in 1α-hydroxylase knockout mice. In contrast to 1α,25-dihydroxyvitamin D3 (1,25-D3 or calcitriol), a naturally occurring VDR agonist, VDR 4-1 therapy even at high doses did not induce hypercalcemia. These findings were accompanied by a lack of upregulation of calcium transport genes in kidney and in the gut providing a mechanism for the lack of hypercalcemia. Furthermore, VDR 4-1 therapy significantly suppressed cardiac hypertrophy and progression to heart failure in both vitamin D deficient and normal mice without inducing significant hypercalcemia. In conclusion, we have identified a unique VDR agonist compound with beneficial effects in mouse models of hyperparathyroidism and heart failure without inducing significant hypercalcemia.Santosh A. KhedkarMohammed A. SamadSangita ChoudhuryJi Yoo LeeDongsheng ZhangRavi I. ThadhaniS. Ananth KarumanchiAlan C. RigbyPeter M. KangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Santosh A. Khedkar Mohammed A. Samad Sangita Choudhury Ji Yoo Lee Dongsheng Zhang Ravi I. Thadhani S. Ananth Karumanchi Alan C. Rigby Peter M. Kang Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
description	Abstract Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that activate the vitamin D receptor (VDR), but are devoid of hypercalcemia. A lead compound (known as VDR 4-1) demonstrated potent transcriptional activities in a VDR reporter gene assay, and significantly ameliorated cardiac hypertrophy in cell culture studies and in animal models. VDR 4-1 also effectively suppressed secondary hyperparathyroidism in 1α-hydroxylase knockout mice. In contrast to 1α,25-dihydroxyvitamin D3 (1,25-D3 or calcitriol), a naturally occurring VDR agonist, VDR 4-1 therapy even at high doses did not induce hypercalcemia. These findings were accompanied by a lack of upregulation of calcium transport genes in kidney and in the gut providing a mechanism for the lack of hypercalcemia. Furthermore, VDR 4-1 therapy significantly suppressed cardiac hypertrophy and progression to heart failure in both vitamin D deficient and normal mice without inducing significant hypercalcemia. In conclusion, we have identified a unique VDR agonist compound with beneficial effects in mouse models of hyperparathyroidism and heart failure without inducing significant hypercalcemia.
format	article
author	Santosh A. Khedkar Mohammed A. Samad Sangita Choudhury Ji Yoo Lee Dongsheng Zhang Ravi I. Thadhani S. Ananth Karumanchi Alan C. Rigby Peter M. Kang
author_facet	Santosh A. Khedkar Mohammed A. Samad Sangita Choudhury Ji Yoo Lee Dongsheng Zhang Ravi I. Thadhani S. Ananth Karumanchi Alan C. Rigby Peter M. Kang
author_sort	Santosh A. Khedkar
title	Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_short	Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_full	Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_fullStr	Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_full_unstemmed	Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia
title_sort	identification of novel non-secosteroidal vitamin d receptor agonists with potent cardioprotective effects and devoid of hypercalcemia
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/853bea727f7e4295a02ec950760e473a
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Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and ﻿﻿devoid of Hypercalcemia

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Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia