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 ¼ 7.1 AE 1.6 nM) and induced osteocalcin promoter activity (EC 50 ¼ 1.9 AE 1.6 nM). VDRM2 was less potent in inducing Ca 2þ channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC 50 ¼ 37 AE 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 mg/kg per day. Hypercalcemia was observed at a dose of 4.6 mg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35-91]. 1a,25-dihydroxyvitamin D 3 [1a,25(OH) 2 D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046 mg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23 mg/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 boneformation 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. ß

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…It was generally well tolerated and restored bone mass, spatial architecture, and bone strength, but it was not as potent as ED71 or 1,25-(OH) 2 D 3 . However, hypercalcemia was not observed in animals until 4.6 mg/kg, indicating a therapeutic safety margin of 57-fold between bone efficacy and hypercalcemia, which is significantly greater than ED-71, 1,25-(OH) 2 D 3 , and alfacalcidol (Sato et al, 2010). If the data from this study are relevant to the clinical trials with ED-71, VDRM2 may have clinical efficacy to treat osteoporosis as well as other disorders, either alone or in combination with other approved therapies.…”

“…In addition, these agents are not orally bioavailable and do not rebuild bone once it has been lost. With this in mind, Sato et al (2010) identified VDRM2, Nuclear Receptors and Their Selective Modulators a nonsecosteroidal, tissue-selective, orally bioavailable VDR ligand. This analog induced VDR-RXR heterodimerization (EC 50 7.1 nM) and stimulated the expression of the bone genes (osteocalcin) in a manner similar to ED-71 and alfacalcidol.…”

Repurposing a novel parathyroid hormone analogue to treat hypoparathyroidism

“…With respect to serum calcium ( Figure 2C), treatment with LY627-2K results in a modest increase across the dose range. Treatment with LY627-2K, within the tested dose range, does not result in hypercalcaemia, i.e., values above the normal threshold level (112 mg·L À1 ) in this model (Sato et al, 2010).…”

Non-secosteroidal Ligands and Modulators

“…78.3), it contains a novel amide side chain, displays good affinity for VDR (K i ¼ 57.8 nM), and is a potent inducer of RXR-VDR heterodimerization (EC 50 ¼ 7.1 nM). VDRM2 induces osteocalcin-promoter activity with an EC 50 of 1.9 nM as compared to 1.3 nM for 1a,25(OH) 2 D 3 , while being less potent in calcium channel TRPV6 upregulation than 1a,25(OH) 2 D 3 with an EC 50 of 37.2 nM compared to that of 0.6 nM for 1a,25(OH) 2 D 3 [15].…”