Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Inhibitors of plasma kallikrein

A compound, selected technology, applied in medical preparations containing active ingredients, active ingredients of heterocyclic compounds, organic chemistry, etc., can solve problems such as short half-life, limited to acute research, etc.

Inactive Publication Date: 2009-07-29
ACTIVESITE PHARMA INC
View PDF16 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, peptide drugs have many drawbacks, including being limited to acute studies because of their short half-lives, requiring medical intervention by intravenous injection, and the development of anti-peptide antibodies in treated patients

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
  • Inhibitors of plasma kallikrein
  • Inhibitors of plasma kallikrein
  • Inhibitors of plasma kallikrein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] Synthesis of PK-specific inhibitors

[0157] Using PS-carbodiimide (obtained from Biotage, Inc., Charlottesville, Virginia) and the synthetic scheme provided by Biotage (see Figure 1), the Carboxylic acid (from ASDI Co., Ltd., Kyiv, Ukraine, or Enamine Co., Ltd.) and 4-amidino-benzylamine (4-AmBz, from Astarte, Bristol, Pennsylvania) Co., Ltd. (Astatech, Inc.)) to form an amide bond to synthesize the compound of the present invention. For each synthesis, 100 micromoles of PS-carbon Diimine with a carboxylic acid (75 μmol), 4-AmBz.2HCl (75 μmol), N-hydroxybenzotriazole (HOBt; 75 μmol) and diisopropylethylamine (DIPEA; 75 micromoles) and mixed on an Adams Nutator (Adams Nutator) at room temperature for 48-72 hours. The product was obtained by filtration, then evaporated to remove DCM. The residual amount of uncoupled 4-AmBZ was determined by quantification of free amine functional groups on 4-AmBZ with ninhydrin, whereby it was determined that more than 95% of the carbo...

Embodiment 2

[0159] Example 2: Research on the inhibitory effect of PK inhibitors

[0160] Human plasma kallikrein (PK) was obtained from Haemtech Technologies, Essex Junction, Vermont. The enzymatic activity of PK was measured with synthetic peptide substrate H-D-Pro-Phe-Arg-pNA (Bachem, Inc., Switzerland), and the cleavage of the substrate by the enzyme would result in A 405 Elevated, which can be used by Molecular Devices (Molecular Devices) V max Dynamic microplate reader to measure. In each well of a microplate reader plate, add 190 μl of PK solution (1 nM in 0.05M HEPES, pH 7.5, 0.01% Triton X-100) to 10 μl of H-D-Pro-Phe-Arg-pNA (2mM, contained in DMSO), shake and mix immediately, measure A in 120-180 seconds 405 The rate of increase of , thus determining the uninhibited PK activity (control). In a parallel experiment, the compound of the present invention was mixed with the synthetic substrate in each well to achieve a final concentration of 0.01-10 micromolar, the volume of th...

Embodiment 3

[0175] Determination of anticoagulant activity of PK inhibitors

[0176] To determine the role of PK on thrombin generation, fibrin cleavage, and ultimately fibrin clot formation upon activation of the intrinsic pathway, contact activation of the intrinsic pathway was initiated using commercially available Actin FS reagent (Dade-Behring) . Human plasma (50 μl) was mixed with 15 mM CaCl in each well of a clean polystyrene 96-well microplate. 2 Actin FS (50 μl) was mixed, passed through a dynamic microplate reader (Molecular Devices (Molecular Devices) V max ) to monitor A 405 , and correlating it with time, thereby determining the timing and extent of fibrin lysis and clot formation. Clot formation leads to increased turbidity, manifested as A 405 Increase. This was confirmed by visual inspection at the end of each experiment. Clotting time is defined as reaching 1 / 2 the maximum ΔA 405 time. All data points are plotted as mean±SD of triplicate wells (n=3).

[0177] Und...

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 present invention provides compounds that inhibit the activity of plasma kallikrein (PK) and methods of preventing and treating the formation of thrombin during or after a PK dependent disease or condition, for example, after fibrinolysis treatment.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application No. 60 / 919,031, filed May 20, 2007, and U.S. Provisional Patent Application No. 60 / 834,377, filed July 31, 2006, the contents of which are incorporated in their entirety This article is for reference. [0003] Claims to Invention under Federally Sponsored Research or Development [0004] Not applicable [0005] For a "sequence listing," a table or computer program listing appendix filed on disk [0006] Not applicable Background of the invention [0007] Thrombosis is necessary to stop blood loss and achieve repair of damaged blood vessels, a process called hemostasis, but it can also be pathogenic when clots block blood vessels and deprive tissues of oxygen. Blockage of arteries by blood clots, known as arterial thrombosis, often occurs at the site of ruptured or eroded atherosclerotic plaques. (Kou, V. et al. (2006) Mt. Sinai J. Med. 73:449-46...

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): C07D401/04C07D401/06C07D209/42C07D231/14C07D249/04C07D277/56C07D207/34C07D333/38C07D333/68C07D307/54C07D307/85A61K31/341A61K31/343A61K31/381A61K31/402A61K31/40A61K31/404A61K31/415A61K31/4192A61K31/426A61K31/4436A61K31/4439
Inventor S·辛哈T·J·奇尔科特
Owner ACTIVESITE PHARMA INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com