title: VS-105: a novel vitamin D receptor modulator with cardiovascular protective effects.
abstract: OBJECTIVE
  Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRM therapy may be associated with cardio-renal protective and survival benefits for CKD patients. However, hypercalcaemia remains a serious side effect for current VDRMs, which leads to the need for frequent dose titration and serum Ca (calcium) monitoring. Significant clinical benefits can be derived from a VDRM with cardiovascular protective effects without the hypercalcaemic liability.
  
  
  METHODS
  Male Sprague-Dawley rats were 5/6 nephrectomized and 6 weeks later, after they had established uraemia, elevated parathyroid hormone levels, endothelial dysfunction and left ventricular hypertrophy, the rats were treated with VS-105, a novel VDRM. The effects of VS-105 were also tested in cultured HL-60 cells.
  
  
  RESULTS
  VS-105 induced HL-60 cell differentiation with an EC₅₀ value at 11.8 nM. Treatment (i.p., 3× a week over a period of 2 weeks) of the 5/6 nephrectomized rats by VS-105 (0.004-0.64 µg·kg⁻¹) effectively suppressed serum parathyroid hormone without raising serum Ca or phosphate levels. Furthermore, 2 weeks of treatment with VS-105 improved endothelium-dependent aortic relaxation and attenuated left ventricular abnormalities in a dose range that did not affect serum Ca levels. Similar results were obtained when VS-105 was administered i.p. or by oral gavage.
  
  
  CONCLUSIONS
  VS-105 exhibits an overall therapeutic product profile that supports expanded use in CKD to realize the cardiovascular protective effects of VDR activation.
authors.affiliation: Vidasym, Chicago, IL 60612, USA. ruth.wuwong@prodigy.net
authors.forename: J Ruth
authors.initials: JR
authors.lastname: Wu-Wong
authors.forename: Megumi
authors.initials: M
authors.lastname: Kawai
authors.forename: Yung-Wu
authors.initials: YW
authors.lastname: Chen
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D004333:Drug Administration Routes; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology; D018922:HL-60 Cells; D006352:Heart Ventricles / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009392:Nephrectomy / Q000379:methods; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors / Q000097:blood; D010710:Phosphates / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014664:Vasodilation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism*
chemical_list: C570781:5-(2-(1-(1-(3-hydroxy-2,3-dimethylbutoxy)ethyl)-7alpha-methyldihydro-1H-inden-4(2H,5H,6H,7H,7alphaH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol; D002316:Cardiotonic Agents; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D010710:Phosphates; D018167:Receptors, Calcitriol; C084656:paricalcitol; D002117:Calcitriol; D002118:Calcium