Two Novel Vitamin D Receptor Modulators with Similar Structures Exhibit Different Hypercalcemic Effects in 5/6 Nephrectomized Uremic Rats

Abstract

Background/Aims: 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 EC₅₀ <0.1 n<smlcap>M</smlcap>. 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.