Last update 01 Nov 2024

HMG-CoA reductase x VDR

Last update 01 Nov 2024

Basic Info

Related Targets

HMG-CoA reductaseVDR

Drugs associated with HMG-CoA reductase x VDR

Olpadronate(Gador SA)

Target

HMG-CoA reductase x VDR

Mechanism

HMG-CoA reductase inhibitors [+1]

Active Org.-

Originator Org.

Gador SA

Active Indication-

Inactive Indication

Hypercalcemia [+2]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with HMG-CoA reductase x VDR

EUCTR2015-004269-96-NL / Unknown statusNot Applicable

A 24 weeks multicentre, randomized, double-blind, placebo-controlled, parallel group, study to evaluate the efficacy, safety and tolerability of intravenous IG-8801 20 mg and 40 mg in subjects with chronic low back pain

Start Date24 Feb 2016

Sponsor / Collaborator-

100 Clinical Results associated with HMG-CoA reductase x VDR

100 Translational Medicine associated with HMG-CoA reductase x VDR

0 Patents (Medical) associated with HMG-CoA reductase x VDR

Literatures (Medical) associated with HMG-CoA reductase x VDR

17 Aug 2023·Microbiology spectrum

Piscine Vitamin D Receptors Vdra/Vdrb in the Absence of Vitamin D Are Utilized by Grass Carp Reovirus for Promoting Viral Replication.

Article

Author: Xiao, Jun ; Xu, Zhen ; Zhang, Jie ; Feng, Hao ; Song, Yun Jie ; Nie, Pin ; Chang, Ming Xian

The vitamin D receptor (VDR) plays a pivotal role in the biological actions of vitamin D (VitD). However, little is known about the functions of VDR in the production of viral inclusion bodies (VIBs). Using a representative strain of grass carp reovirus (GCRV) genotype I, GCRV-873, we show that GCRV-873 recruits grass carp Vdrs for promoting the production of VIBs in the absence of VitD. Inhibition of cholesterol synthesis by lovastatin impairs the production of VIBs and blocks the effects of grass carp Vdrs in promoting the production of VIBs in the absence of VitD. Furthermore, grass carp Vdrs are found to form the Vdra-Vdrb heterodimer, which is vital for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (hmgcr)-dependent cholesterol synthesis and GCRV replication. Intriguingly in the presence of VitD, grass carp Vdra but not Vdrb forms the heterodimer with the retinoid X receptor beta b (Rxrbb), which induces the transcription of those genes involved in the RIG-I-like receptor (RLR) antiviral signaling pathway for inhibiting GCRV infection. Furthermore, the VitD-activated Vdra-Vdrb heterodimer attenuates the transcription of the RLR antiviral signaling pathway induced by VitD. In the presence of VitD, a balance between the Vdra-Rxrbb heterodimers as coactivators and Vdra-Vdrb heterodimers as corepressors in affecting the transcriptional regulation of the RLR antiviral signaling pathway may eventually determine the outcome of GCRV infection. Transfection with VitD can abolish the effect of grass carp Vdrs in promoting GCRV replication in a dose-dependent manner. Taken together, these findings demonstrate that GCRV utilizes host Vdrs to increase hmgcr-dependent cholesterol synthesis for promoting its replication, which can be prevented by VitD treatment. IMPORTANCE Grass carp reovirus (GCRV) is the causative agent of grass carp hemorrhagic disease, which seriously harms freshwater fish. Although many positive or negative regulators of GCRV infection have been identified in teleosts, little is known about the molecular mechanisms by which GCRV utilizes host factors to generate its infectious compartments beneficial for viral replication and infection. Here, we show that in the absence of VitD, the GCRV-873 strain utilizes host vitamin D receptors Vdra/Vdrb to increase hmgcr-dependent cholesterol synthesis for promoting the production of VIBs, which are important functional sites for aquareovirus replication and assembly. The negative regulation of Vdrs during viral infection can be prevented by VitD treatment. Thus, this present work broadens understanding of the pivotal roles of Vdrs in the interaction between the host and GCRV in the absence or presence of VitD, which might provide a rational basis for developing novel anti-GCRV strategies.

01 Jan 2018·Drug Metabolism and DispositionQ2 · MEDICINE

Highlighting Vitamin D Receptor–Targeted Activities of 1α,25-Dihydroxyvitamin D₃in Mice via Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling

Q2 · MEDICINE

Article

Author: Chow, Edwin C Y ; Bukuroshi, Paola ; Yang, Qi Joy ; Quach, Holly P ; Pang, K Sandy

We expanded our published physiologically based pharmacokinetic model (PBPK) on 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], ligand of the vitamin D receptor (VDR), to appraise VDR-mediated pharmacodynamics in mice. Since 1,25(OH)₂D₃ kinetics was best described by a segregated-flow intestinal model (SFM) that described a low/partial intestinal (blood/plasma) flow to enterocytes, with feedback regulation of its synthesis (Cyp27b1) and degradation (Cyp24a1) enzymes, this PBPK(SFM) model was expanded to describe the VDR-mediated changes (altered/basal mRNA expression) of target genes/responses with the indirect response model. We examined data on 1) renal Trpv5 (transient receptor potential cation channel, subfamily V member 5) and Trpv6 and intestinal Trpv6 (calcium channels) for calcium absorption; 2) liver 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) and cytochrome 7α-hydroxylase (Cyp7a1) for cholesterol synthesis and degradation, respectively; and 3) renal and brain Mdr1 (multidrug-resistance protein that encodes the P-glycoprotein) for digoxin disposition after repetitive intraperitoneal doses of 120 pmol 1,25(OH)₂D₃ Fitting, performed with modeling software, yielded reasonable prediction of a dominant role of intestinal Trpv6 in calcium absorption, circadian rhythm that is characterized by simple cosine models for Hmgcr and Cyp7a1 on liver cholesterol, and brain and renal Mdr1 on tissue efflux of digoxin. Fitted parameters on the E_max, EC₅₀, and turnover rate constants of VDR-target genes [zero-order production (k_in) and first-order degradation (k_out) rate constants] showed low coefficients of variation and acceptable median prediction errors (4.5%-40.6%). Sensitivity analyses showed that the E_max and EC₅₀ values are key parameters that could influence the pharmacodynamic responses. In conclusion, the PBPK(SFM)-pharmacodynamic model successfully characterized VDR gene activation and serves as a useful tool to predict the therapeutic effects of 1,25(OH)₂D₃.

01 May 2009·Mini-Reviews in Medicinal ChemistryQ3 · MEDICINE

Diphenylpentane Skeleton as a Multi-Template for Steroid Skeleton- Recognizing Receptors/Enzymes

Q3 · MEDICINE

Review

Author: Hosoda, Shinnosuke ; Hashimoto, Yuichi ; Matsuda, Daisuke ; Tomoda, Hiroshi

As an example of a multi-template approach, we focused on the 3,3-diphenylpentane (DPP) skeleton, which has been demonstrated to act as a steroid skeleton substitute. Various ligands for nuclear receptors (NRs), including vitamin D receptor (VDR), androgen receptor (AR) and farnesoid X receptor (FXR), and inhibitors of steroid metabolism-related enzymes, including 5alpha-reductase and HMG-CoA reductase (HMGR), have been efficiently created by introducing various substituents onto the DPP skeleton.

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