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Treatment of neurological conditions using complement c5a receptor modulators

A technology of receptor inhibitors and diseases, applied in the direction of nervous system diseases, cardiovascular system diseases, anti-inflammatory agents, etc., can solve problems such as no evidence

Inactive Publication Date: 2007-07-11
PROMICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] However, to date there is no evidence that inhibitors of the C5a receptor, especially low molecular weight antagonists of this receptor, can be useful in the treatment of neuropathic or neurodegenerative disorders involving inflammation

Method used

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  • Treatment of neurological conditions using complement c5a receptor modulators
  • Treatment of neurological conditions using complement c5a receptor modulators
  • Treatment of neurological conditions using complement c5a receptor modulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0181] Example 1 A pilot study of the role of PMX53

[0182] Preliminary experiments have shown that a dose of 42 mg / kg / day administered for 7 days reproducibly induces this model. To test the effect of PMX53 in this model system, a pilot study was performed. In this study, rats treated with PMX53 were compared to sham-operated and untreated controls. A total of 12 rats were used as follows:

[0183] fake operation 2

[0184] Untreated 5

[0185] PMX53 5

[0186] Daily administration of PMX53 with drinking water at a dose of 2 mg / kg was started two days before 3-NP administration. These PMX53-treated animals were given a dose of 1 mg / kg s.c. on days 0, 3, 6 and 8, and since they were not eating, it was considered possible that they were not drinking. In subsequent experiments, animals were given daily doses by gavage, starting on day 2, to avoid this potential influencing factor. In this initial experiment, the pump was removed after 7 days and the skin was sutured ...

Embodiment 2

[0190] Example 2 Use other substances to compare

[0191]The effect of PMX53 was compared with another compound of formula I, PMX205 (hydrocinnamic acid-[OpdChaWR](HC-[OPdChaWR]) and the known anti-inflammatory agents ibuprofen and infliximab. The groups of rats and the number of each group were as follows :

[0192] fake operation 4

[0193] Untreated 6

[0194] PMX53 4

[0195] PMX205 4

[0196] ibuprofen 5

[0197] Infliximab 4

[0198] PMX53 (10 mg / kg / day) and PMX205 (10 mg / kg / day) were administered daily by gavage and ibuprofen (30 mg / kg / day) was administered in drinking water, starting two days before 3-NP administration. Infliximab was administered intravenously as a single dose of 5 mg / kg on day 0.

[0199] The results are shown in Figures 3A-3D. Figures 2A and 2B show that the extent of body weight gain and food consumption after 7 days is similar to that observed in Example 1. For neurologic / behavioral scores, both PMX53 and PMX205 had significant protec...

Embodiment 3

[0209] Example 3 Effects of PMX53 analogues

[0210] The following compounds of formula I were tested in the same manner as described in Example 2:

[0211] PMX205: HC-[OPdChaWR]

[0212] PMX273: AcF-[OPdPheWR]

[0213] PMX201: AcF-[OPdChaW citrulline]

[0214] PMX218: HC-[OPdPheWR]

[0215] Starting on day 2, all drugs were administered by gavage at a dose of 10 mg / kg / day. If this dose is found to be effective, the 3 mg / kg / day and 1 mg / kg / day or less doses are retested in order to determine the dose-response relationship. The dose-response relationship of PMX53 was also determined.

[0216] The effects of these substances were also compared with those of infliximab (infliximab (in a single dose of 5 mg / kg iv on day 0) and ibuprofen (30 mg / kg) given through drinking water.

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Abstract

This invention relates to the treatment of neurological conditions with novel cyclic peptidic and peptidomimetic compounds which have the ability to modulate the activity of C5a receptors. The compounds preferably act as antagonists of the C5a receptor, and are active against C5a receptors on polymorphonuclear leukocytes, monocytes, lymphocytes and / or macrophages. In a preferred form of the invention the neurological conditions are neurodegenerative diseases, neuroimmunological disorders, diseases arising from dysfunction of the blood brain barrier, and stroke.

Description

field of invention [0001] The present invention relates to the use of novel cyclic polypeptides and peptidomimetic compounds having the ability to modulate C5a receptor activity in the treatment of neurological disorders. The compounds preferably act as antagonists of the C5a receptor and are active at the C5a receptor on polymorphonuclear leukocytes, monocytes, lymphocytes and / or macrophages. In a preferred embodiment of the present invention, the neurological disorder is a neurodegenerative disease, a neuroimmune disorder, a disease caused by a dysfunction of the blood-brain barrier, and stroke. Background of the invention [0002] All references cited, including any patents or patent applications, are hereby incorporated by reference. Without admission, any cited document does not constitute prior art. The discussion of the references states that the authors request, and the applicants reserve the right to challenge, the accuracy and pertinence of the cited documents. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/12A61P25/28
CPCA61K38/12A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/28A61P29/00A61P43/00A61P9/10A61K2300/00
Inventor 特伦特·马丁·伍德拉夫斯蒂芬·马克斯韦尔·泰勒
Owner PROMICS
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