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Inhibitors of interleukin-1beta converting enzyme

a technology of interleukin-1beta and converting enzyme, which is applied in the direction of antibacterial agents, peptide/protein ingredients, dipeptides, etc., can solve the problems of poor oral absorption, poor cellular penetration and cellular activity, and unsatisfactory pharmacologic properties, so as to improve cellular potency, inhibit the activity of the enzyme, and treat or prevent diseases

Inactive Publication Date: 2005-06-30
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0020] The present invention provides novel classes of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of ICE. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antibiotics, immunomodulators or other anti-inflammatory agents, for the treatment or prophylaxis of diseases mediated by IL-1, apoptosis, IGIF or IFN-γ. According to a preferred embodiment, the compounds of this invention are capable of binding to the active site of ICE and inhibiting the activity of that enzyme. Additionally, they have improved cellular potency, improved pharmacokinetics, and / or improved oral bioavailability compared to peptidyl ICE inhibitors.

Problems solved by technology

However, due to their peptidic nature, such inhibitors are typically characterized by undesirable pharmacologic properties, such as poor cellular penetration and cellular activity, poor oral absorption, poor stability and rapid metabolism.
This has hampered their development into effective drugs.
2438-2440 (1996); However, it is not clear whether these compounds have the appropriate pharmacological profile to be therapeutically useful.
Additionally, current methods for the preparation of such compounds are not advantageous.
These methods use tributyltin hydride, a toxic, moisture sensitive reagent.
Thus, these methods are inconvenient to carry out, pose a health risk and create toxic-waste disposal problems.
Furthermore, it is difficult to purify compounds prepared by these methods.

Method used

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  • Inhibitors of interleukin-1beta converting enzyme
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  • Inhibitors of interleukin-1beta converting enzyme

Examples

Experimental program
Comparison scheme
Effect test

example 1

Inhibition of ICE

[1757] We obtained inhibition constants (Ki) and IC50 values for compounds of this invention using the three methods described below:

1. Enzyme Assay with UV-Visible Substrate

[1758] This assay is run using an Succinyl-Tyr-Val-Ala-Asp-pNitroanilide substrate. Synthesis of analogous substrates is described by L. A. Reiter (Int. J. Peptide Protein Res. 43, 87-96 (1994)). The assay mixture contains: [1759] 65 μl buffer (10 mM Tris, 1 mM DTT, 0.1% CHAPS @pH 8.1) [1760] 10 μl ICE (50 nM final concentration to give a rate of ˜1 mOD / min) [1761] 5 μl DMSO / Inhibitor mixture [1762] 20 μl 400 μM Substrate (80 μM final concentration) [1763] 100 μl total reaction volume

[1764] The visible ICE assay is run in a 96-well microtiter plate. Buffer, ICE and DMSO (if inhibitor is present) are added to the wells in the order listed. The components are left to incubate at room temperature for 15 minutes starting at the time that all components are present in all wells. The microtiter p...

example 2

Pharmacokinetic Studies in the Mouse

[1784] Peptidyl ICE inhibitors are cleared rapidly with clearance rates greater than 100 μ / min / kg. Compounds with lower clearance rates have improved pharmacokinetic properties relative to peptidyl ICE inhibitors.

[1785] We obtained the rate of clearance in the mouse (μ / min / kg) for several compounds of this invention using the method described below:

Sample Preparation and Dosing

[1786] Compounds were dissolved in sterile TRIS solution (0.02M or 0.05M) at a concentration of 2.5 mg / ml. Where necessary to ensure a complete solution, the sample was first dissolved in a minimum of dimethylacetamide (maximum of 5% of total solution volume) then diluted with the TRIS solution.

[1787] The drug solution was administered to CD-1 mice (Charles River Laboratories—26-31 g) via the tail vein at a dose volume of 10 ml / kg giving a drug dose of 25 mg / kg.

[1788] Mice were dosed in groups of 5 for each timepoint (generally from 2 minutes to 2 hours) then at the a...

example 3

[1798] Peptidyl ICE inhibitors are cleared rapidly with clearance rates greater than 80 ml / min / kg. Compounds with lower clearance rates have improved pharmacokinetic properties relative to peptidyl ICE inhibitors.

[1799] We obtained the rate of clearance in the rat (ml / min / kg) for several compounds of this invention using the method described below:

In Vivo Rat Clearance Assay

[1800] Cannulations of the jugular and carotid vessels of rats under anesthesia were performed one day prior to the pharmacokinetic study. M. J. Free, R. A. Jaffee; ‘Cannulation techniques for the collection blood and other bodily fluids’; in: Animal Models; p. 480-495; N. J. Alexander, Ed.; Academic Press; (1978). Drug (10 mg / mL) was administered via the jugular vein in a vehicle usually consisting of: propylene glycol / saline, containing 100 mM sodium bicarbonate in a 1:1 ratio. Animals were dosed with 10-20 mg drug / kg and blood samples were drawn at 0, 2, 5, 7, 10, 15, 20, 30, 60, and 90 minutes from an indw...

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PUM

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Abstract

The present invention relates to novel classes of compounds which are inhibitors of interleukin-1β converting enzyme. The ICE inhibitors of this invention are characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against IL-1-, apoptosis-, IGIF-, and IFN-γ-mediated diseases, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, degenerative diseases, and necrotic diseases. This invention also relates to methods for inhibiting ICE activity, for treating interleukin-1-, apoptosis-, IGIF- and IFN-γ-mediated diseases and decreasing IGIF and IFN-γ production using the compounds and compositions of this invention. This invention also relates to methods for preparing N-acylamino compounds.

Description

TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to novel classes of compounds which are inhibitors of interleukin-1β converting enzyme (“ICE”). This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against interleukin-1- (“IL-1”), apoptosis-, interferon gamma inducing factor- (“IGIF”) and interferon-γ- (“IFN-γ”) mediated diseases, including inflammatory diseases, autoimmune diseases, destructive bone, proliferative disorders, infectious diseases and degenerative diseases. This invention also relates to methods for inhibiting ICE activity, and decreasing IGIF production and IFN-γ production and methods for treating interleukin-1-, apoptosis-, IGIF- and IFN-γ-mediated diseases using the compounds and compositions of this invention. This invention also relate...

Claims

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Application Information

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IPC IPC(8): A61K31/55A61K31/551A61K31/553C07D243/12A61K31/675A61K38/00A61K38/04A61K38/05A61K38/06A61K38/07A61K38/55A61P13/12A61P19/08A61P19/10A61P25/00A61P25/28A61P29/00A61P31/00A61P31/04A61P35/00A61P37/00A61P37/06A61P43/00C07D243/10C07D243/14C07D401/12C07D403/12C07D405/12C07D409/12C07D413/12C07D417/12C07D471/04C07D473/00C07D487/04C07D491/048C07D495/04C07D498/04C07D513/04C07D519/00C07F9/645C07F9/6561C07K5/02C07K5/023C07K5/06C07K5/078C07K5/097
CPCA61K38/00C07D243/12C07D401/06C07D401/12C07D403/12C07D405/12C07D405/14C07D409/12C07D413/12C07D417/12C07D471/04C07D487/04C07K5/0202C07K5/06139C07K5/0821A61P1/00A61P1/04A61P1/16A61P1/18A61P11/00A61P11/06A61P13/12A61P17/00A61P17/02A61P17/04A61P17/06A61P17/14A61P19/00A61P19/02A61P19/08A61P19/10A61P21/00A61P21/04A61P25/00A61P25/16A61P25/28A61P29/00A61P3/00A61P31/00A61P31/04A61P31/18A61P35/00A61P35/02A61P35/04A61P37/00A61P37/06A61P37/08A61P43/00A61P5/14A61P7/00A61P7/04A61P7/06A61P9/00A61P9/10A61P3/10C07K5/02C07D498/04A61K31/55
Inventor BATCHELOR, MARKBEBBINGTON, DAVIDBEMIS, GUYFRIDMAN, WOLFGILLESPIE, ROGERGOLEC, JULIANLAUFFER, DAVIDLIVINGSTON, DAVIDMATHARU, SAROOPMULLICAN, MICHAELMURCKO, MARKMURDOCH, ROBERTZELLE, ROBERT
Owner VERTEX PHARMA INC
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