title: A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia.
abstract: Vitamin D(3) analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC(50) = 7.1 +/- 1.6 nM) and induced osteocalcin promoter activity (EC(50) = 1.9 +/- 1.6 nM). VDRM2 was less potent in inducing Ca(2+) channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC(50) = 37 +/- 12 nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08 microg/kg per day. Hypercalcemia was observed at a dose of 4.6 microg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35-91]. 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046 microg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23 microg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1-13, 3.2-7.7, and 3.5-6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal bone-formation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential.
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA. sato_masahiko@lilly.com
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sato
authors.forename: Jianliang
authors.initials: J
authors.lastname: Lu
authors.forename: Stephen
authors.initials: S
authors.lastname: Iturria
authors.forename: Keith R
authors.initials: KR
authors.lastname: Stayrook
authors.forename: Lorri L
authors.initials: LL
authors.lastname: Burris
authors.forename: Qing Qiang
authors.initials: QQ
authors.lastname: Zeng
authors.forename: Allen
authors.initials: A
authors.lastname: Schmidt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Barr
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Henry U
authors.initials: HU
authors.lastname: Bryant
authors.forename: Yanfei L
authors.initials: YL
authors.lastname: Ma
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001681:Biological Assay; D001696:Biomechanical Phenomena / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000150:complications / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology*; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D050916:TRPV Cation Channels; C120776:TRPV6 channel; D015675:Osteocalcin; D002762:Cholecalciferol; D008156:Luciferases