title: Synthesis of VS-105: A novel and potent vitamin D receptor agonist with reduced hypercalcemic effects.
abstract: We have synthesized a novel vitamin D receptor agonist VS-105 ((1R,3R)-5-((E)-2-((3αS,7αS)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)-7α-methyldihydro-1H-inden-4(2H,5H,6H,7H,7αH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol). Preparation of a-ring phenylphosphine oxide 11, followed by Wittig-Horner coupling of 11 with the protected 25-hydroxy Grundmann's ketone 22 generated the precursor 12. Deprotection of the TBDMS groups of 12 produced the target compound VS-105. The biological profiles of VS-105 were evaluated using in vitro assays (VDR receptor binding, VDR reporter gene and HL-60 differentiation) in comparison to calcitriol (the endogenous hormone) or paricalcitol. Furthermore, the PTH suppressing potency and hypercalcemic side effects of VS-105 were evaluated in the 5/6 nephrectomized uremic rats in comparison to paricalcitol. Combining various changes at 20-epi, 22-oxa, 24-methyl, and 2-methylene yielded VS-105 that not only is highly potent in inducing functional responses in vitro, but also effectively suppresses PTH in a dose range that does not affect serum calcium in the 5/6 nephrectomized uremic rats.
authors.affiliation: Vidasym, 2201 W. Campbell Park Dr., Suite 13, Chicago, IL 60612, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Chen
authors.forename: Megumi
authors.initials: M
authors.lastname: Kawai
authors.forename: J Ruth
authors.initials: JR
authors.lastname: Wu-Wong
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004872:Ergocalciferols / Q000009:adverse effects; D018922:HL-60 Cells; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000139:chemically induced; D010281:Parathyroid Hormone / Q000378:metabolism; D051381:Rats; D018167:Receptors, Calcitriol / Q000819:agonists* / 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; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; C084656:paricalcitol; D002117:Calcitriol; D002118:Calcium
keywords: CKD; Ca; Hypercalcemia; Hyperparathyroidism; NX; PTH; Pi; VDR; VDR modulators; VDRMs; Vitamin D analog; Vitamin D receptor; calcium; chronic kidney disease; nephrectomized; parathyroid hormone; phosphate; vitamin D receptor