FGFR inhibitor for use in the treatment of hypophosphatemic disorders

Inactive Publication Date: 2015-03-12
NOVARTIS AG
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  • Abstract
  • Description
  • Claims
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Benefits of technology

[0012]Another aspect of the invention is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use in increasing cortical bone volume or thickness when compared to a control or cortical bone volume or thickness before the beginning of the treatment.
[0013]Yet another aspect of the invention is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin

Problems solved by technology

Current therapeutic approaches to these diseases are mainly limited to dietary vitamin D and phosphate supplementation.
Althou

Method used

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  • FGFR inhibitor for use in the treatment of hypophosphatemic disorders
  • FGFR inhibitor for use in the treatment of hypophosphatemic disorders
  • FGFR inhibitor for use in the treatment of hypophosphatemic disorders

Examples

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example 1

[0036]FGFR inhibitor treatment induces 1,25(OH)2D3 biosynthesis and alleviates hypocalcemia and hypophosphatemia in Hyp mice. Wild-type C57BL / 6 and Hyp (B6.Cg-PhexHyp / J) mice were obtained from The Jackson Laboratory. Dmp1-null mice were generated by Feng et al. (J. Dent. Res. 2003; 82:776-780.). All mice were kept in cages under standard laboratory conditions. Mice were fed on a standard rodent diet with water ad libitum.

[0037]Wild-type or Hyp mice received a single oral dose of the FGFR inhibitor BGJ398 in its free base form (50 mg / kg) or vehicle and were studied 7 h after administration of the compound. BGJ398 or vehicle only (PEG-300 / Glucose 5%, 2:1 mix) was administered by oral gavage. Mice were used at 5-7 weeks of age in the case of single dose administrations. Mice were anesthetized by isoflurane inhalation and blood was collected from the caval vein. Mice were sacrificed by exsanguination and kidney and tibial and femoral bones were obtained. Concentrations of BGJ398 in kid...

example 2

[0045]FGFR inhibitor treatment modulates renal FGF23 target gene expression and alleviates hypocalcemia and hypophosphatemia in Dmp1-null mice. Regulation of the renal FGF23 target genes Cyp27b1 (FIG. 2A) and Cyp24a1 (FIG. 2B) upon FGFR inhibition in vivo is shown on FIG. 2. In addition to our findings in the Phex-deficient Hyp model, we observed a similar regulation of renal Cyp27b1 and Cyp24a1 expression in Dmp1-null mice, another FGF23-related hypophosphatemia model (FIGS. 2A and B). Wild-type or Dmp1-null mice received a single oral dose of the FGFR inhibitor BGJ398 (50 mg / kg) or vehicle and were again studied 7 h after administration of the compound. As before, kidneys were sampled, total RNA was isolated and gene expression was analyzed by qPCR. Expression values were normalized to Gapdh mRNA copies. Data in A and B are shown as relative levels to the wild-type vehicle control group and are given as average with standard errors of the mean (SEM) (n≧6).

[0046]For analysis of cal...

example 3

[0047]FIG. 3 shows FGFR-dependent signaling regulates FGF23 expression in bone. Besides the alleviation of the mineral ion deficiency in the two mouse models for FGF23-related hypophosphatemic rickets, we also noticed a repressive effect of FGFR inhibitor treatment on FGF23 levels in BGJ398-treated Hyp mice. Mice received a single oral dose of the FGFR inhibitor BGJ398 (50 mg / kg) or vehicle and were studied 7 h post-administration. FGF23 bone mRNA (FIG. 3A) and serum (FIG. 3B) levels in wild-type and Hyp mice treated with BGJ398 were determined. At 7 h post-dosing of BGJ398 FGF23 expression in bone of both Hyp and wild-type mice was almost abolished (FIG. 2A). The transcriptional repression of FGF23 resulted in undetectable serum FGF23 levels in wild-type mice, while the pathological high FGF23 levels in Hyp mice were reduced by approximately 50% (FIG. 3B). mRNA expression is shown on the figure as relative levels to the wild-type vehicle control group (relative levels of 100) and a...

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Abstract

The present invention relates generally to 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl)-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemia rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), tumor-induced osteomalacia, post-renal transplant hypophosphatemia, epidermal nevus syndrome, osteoglophonic dysplasia or McCune-Albright syndrome.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl}-1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of the fibroblast growth factor receptor mediated disorders.BACKGROUND OF THE INVENTION[0002]The fibroblast growth factor (FGF) family and their signaling receptors are associated with multiple biological activities (proliferation, survival, apoptosis, differentiation, motility) that govern key processes (development, angiogenesis, and metabolism) for the growth and maintenance of organisms from worms to humans. 22 distinct FGFs have been identified, all sharing a conserved 120-aminoacids core domain with 15-65% se...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K33/42A61K31/59A61K38/17A61K38/29A61K45/06A61K33/06
CPCA61K31/506A61K45/06A61K33/42A61K31/59A61K38/1709A61K38/29A61K33/06A61P3/02A61P3/12A61P3/14A61P7/00A61P17/00A61P19/08A61P19/10A61P35/00A61P39/02A61P43/00A61K2121/00
Inventor KNEISSEL, MICHAELAGAUGNANO, VITOGRAUS PORTA, DIANAWOHRLE, SIMON
Owner NOVARTIS AG
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