Application of compound to preparation of medicament for cathepsin-K-targeted disease

A cathepsin and compound technology, applied in metabolic diseases, bone diseases, digestive system, etc., can solve the problems of inactive site inhibitors, side effects of active site inhibitors, dysfunction of thyroxine release, etc., and achieve inhibition Effects of human osteoclast activity, increasing bone density, improving bone structural characteristics and physiological state

Inactive Publication Date: 2017-07-21
SHANGHAI MUNICIPAL CENT FOR DISEASE CONTROL & PREVENTION
View PDF1 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The study found that in addition to the expected phenotype of the skeletal system, cathepsin K-deficient mice also showed lung airway damage, prone to lung and skin fibrosis, thyroglobulin (Tg) release thyroxine dysfunction, and even led to learning and memory deficits etc., suggesting that active site inhibitors may cause side effects, which poses a challenge for the development of novel anti-osteoporosis drugs
[0005] At present, CatK inhibitor patents at home and abroad are all active site inhibitors, and there is no inactive site inhibitor yet

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Application of compound to preparation of medicament for cathepsin-K-targeted disease
  • Application of compound to preparation of medicament for cathepsin-K-targeted disease
  • Application of compound to preparation of medicament for cathepsin-K-targeted disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Screening and Confirmation of Novel Inactive Site Inhibitors of Cathepsin K

[0039] Seven monomer compounds in Danshen, including type I structure danshenneoquinone D, type II structure dihydrotanshinone I, tanshinone I, tanshinone IIA, cryptotanshinone, sodium tanshinone IIA sulfonate and type III structure table salvianolactone were investigated. Screening for active site inhibitors. The structure is as follows:

[0040]

[0041] 1 Experimental materials

[0042] 1.1 Medicinal materials and reagents

[0043]Monomer compounds tanshinone D, dihydrotanshinone I, tanshinone I, tanshinone IIA, cryptotanshinone, tanshinone IIA sodium sulfonate and epidanshinone cryptospironolactone were purchased from Chemfaces; Benzyloxycarbonyl-Phe-Arg-7-amido-4- Methylcoumarin (Z-FR-MCA) was purchased from Japan WAKO Company; chondroitin sulfate A (C4-S), E-64 (L-3-carboxy-trans-2-3-epoxypropionyl-leucylamido-(4guanidino)-butane) Pepsin and pepsin were purchased from S...

Embodiment 2

[0064] Example 2: Effect of Cathepsin K Inhibitor T06 on Osteoclast Bone Resorption

[0065] Osteoclasts express a rich intracytoplasmic enzyme system, and a series of marker proteins are produced during the differentiation of osteoclast precursor cells to mature osteoclasts, which can be used as markers for the identification of osteoclasts and their differentiation stages. Among them, tartrate-resistant acid phosphatase (TRAP) expressed by differentiated osteoclast precursor cells is considered to be a marker enzyme of osteoclasts. In this experiment, bone marrow-induced osteoclast model was used to investigate the effects of T02 and T06 on osteoclast differentiation and TRAP activity.

[0066] 1 Experimental materials

[0067] 1.1 Medicinal materials and reagents

[0068] Animals: 5 littermate SD mice born 1-2 days old, male or female, weighing 7-8 g, provided by the Experimental Animal Center of Second Military Medical University.

[0069] Tanshinone IIA sodium sulfonat...

Embodiment 3

[0083] Example 3: Effects of Cathepsin K Inhibitor T06 on Ovariectomized Osteoporotic Mice

[0084] 1 Experimental materials

[0085] Animals: C57BL6 mice were provided by the University of British Columbia, Canada. Animals were reared in separate cages (3-4 animals / cage) in an air-conditioned greenhouse at a temperature of 21±2°C and a humidity of 40-60%. They were fed with pellet feed and had free access to water.

[0086] 2 Experimental methods

[0087] Animal grouping: 30 female C57BL6 mice (18-22g) were randomly divided into 3 groups according to body weight, 10 in each group, including sham operation group (SHAM, intragastric administration of normal saline 10ml / kg), osteoporosis model group (OVX, give normal saline 10ml / kg) and T06 (40mg / kg / d) 3 groups. After recovering for 5 days, the drug was given continuously by intragastric administration for 12 weeks.

[0088] Modeling method: Isoflurane anesthesia on the operating table, two 0.5 cm incisions were made on the ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention relates to application of a compound to preparation of a medicament for a cathepsin-K-targeted disease. The compound is a cathepsin K inactive site inhibitor, acts on a cathepsin inactive site, has remarkable collagen and elastic fibrin degradation inhibition activity, and can be used for preparing a medicament for treating a disease characterized by abnormal expression or activation of cathepsin K, comprising osteoporosis, gingival diseases (gingivitis and periodontitis), Paget's diseases, metabolic bone diseases, fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, hypercalcemia, multiple myeloma, metastatic bone diseases and pains, and the influence on the degradation activity of other extracellular substrates is eliminated.

Description

technical field [0001] The present invention relates to the technical field of cathepsin inhibitors, in particular to the application of a cathepsin K non-active site inhibitor with high selectivity in the preparation of a disease drug targeting cathepsin K, the disease Includes osteoporosis, gum disease (gingivitis and periodontitis), Paget's disease, metabolic bone disease, fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, Malignant hypercalcemia, multiple myeloma, metastatic bone disease, and pain. Background technique [0002] There are many conditions related to abnormal bone resorption, including but not limited to osteoporosis, gum disease (gingivitis and periodontitis), Paget's disease, metabolic bone disease, bone fractures, rheumatoid arthritis, osteoarthritis inflammation, periprosthetic osteolysis, osteogenesis imperfecta, malignant hypercalcemia, multiple myeloma, metastatic bone disease, and pain. One of the ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/58A61K31/352A61K31/365A61K31/343A61P19/10A61P1/02A61P19/00A61P19/02A61P3/14
CPCA61K31/58A61K31/343A61K31/352A61K31/365
Inventor D·布罗姆P·潘瓦尔薛黎明
Owner SHANGHAI MUNICIPAL CENT FOR DISEASE CONTROL & PREVENTION
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap