title: Two novel vitamin D receptor modulators with similar structures exhibit different hypercalcemic effects in 5/6 nephrectomized uremic rats.
abstract: OBJECTIVE
  Vitamin D receptor modulators (VDRMs) are indicated for secondary hyperparathyroidism in chronic kidney disease (CKD). Clinical observations demonstrate that VDRM therapy provides cardiovascular (CV) benefit in CKD. Current on-market VDRMs have a narrow therapeutic index at 1- to 4-fold [hypercalcemic toxicity vs. parathyroid hormone (PTH)-suppressing efficacy]. Hypercalcemia leads to the need for frequent drug dose titration and serum calcium (Ca) monitoring. A VDRM with a wider therapeutic index and beneficial CV effects will be clinically useful.
  
  
  METHODS
  Two structurally similar VDRMs were tested in the 5/6 nephrectomized (NX) rats with elevated PTH, endothelial dysfunction and left ventricular hypertrophy.
  
  
  RESULTS
  VS-110 and VS-411 at 0.01-1 μg/kg (i.p. 3 times/week for 2 weeks) suppressed serum PTH effectively. VS-411 raised serum Ca with an 11% increase at 0.01 μg/kg (therapeutic index = ~1-fold), while VS-110 did not raise serum Ca even at 1 μg/kg (therapeutic index >50-fold). VS-110 improved endothelium-dependent aortic relaxation in a dose-dependent manner and significantly reduced left ventricular fibrosis without affecting serum Ca. VS-411 also exhibited effects on the CV parameters, but was less potent at the high doses with severe hypercalcemia. VS-110 and VS-411 specifically activated the reporter gene via a chimeric receptor containing the VDR ligand binding domain with EC(50) <0.1 nM.
  
  
  CONCLUSIONS
  Structurally similar VDRMs can exhibit distinctly different hypercalcemic effects in 5/6 NX uremic rats. While differences exist for the Ca and CV effects of VS-110 and VS-411, the clinical implications are unclear. VS-110's results are promising but clinical outcome studies need to be performed.
authors.affiliation: Vidasym, Chicago, IL, 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: Jerry L
authors.initials: JL
authors.lastname: Wessale
authors.forename: Ching-jang
authors.initials: CJ
authors.lastname: Huang
authors.forename: Meng-ting
authors.initials: MT
authors.lastname: Wu
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakane
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002117:Calcitriol / Q000031:analogs & derivatives*; D002118:Calcium / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000473:pathology; D006934:Hypercalcemia / Q000378:metabolism*; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000209:etiology; D066298:In Vitro Techniques; D008297:Male; D009392:Nephrectomy; D009929:Organ Size; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism*; D012632:Secosteroids / Q000494:pharmacology*; D014511:Uremia / Q000378:metabolism* / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: C583092:5-(2-(1-(1-(3-ethyl-3-hydroxypentyloxy)ethyl)-7-methyldihydro-1H-inden-4(2H,5H,6H,7H,7alphaH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol; C583093:6-(2-(1-(1-(3-ethyl-3-hydroxypentyloxy)ethyl)-7-methyldihydro-1H-inden-4(2H,5H,6H,7H,7alphaH)-ylidene)ethylidene)spiro(2.5)octane-4,8-diol; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D012632:Secosteroids; D010758:Phosphorus; D002117:Calcitriol; D002118:Calcium