Inhibitors of peptide binding to MHC class II proteins

Details Inhibitors of peptide binding to MHC class II proteins Inhibitors of peptide binding to MHC class II proteins

1999-06-14

2001-02-06

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S016700, C530S328000, C530S332000

Reexamination Certificate

active

06184207

ABSTRACT:

The present invention relates to certain novel peptides which possess pharmacologically useful properties for use in treating autoimmune diseases or medical conditions, such as rheumatoid arthritis and other MHC class II dependent T-cell mediated diseases. The invention also includes pharmaceutical compositions of the novel peptides, processes for their manufacture, and their use in treating one or more of the aforementioned diseases or medical conditions and in the production of novel pharmaceuticals for use in such medical treatments.
Stimulation of the human immune response is dependent on the recognition of protein antigens by T cells. However T cells cannot respond to antigen alone and are only triggered by antigen when it is complexed with major histocompatibility complex (MHC) molecules on the surface of an antigen presenting cell, such as a B cell, macrophage or dendritic cell.
MHC class I molecules elicit a T-killer cell response which results in the destruction of the cell bearing the antigen. MHC class II molecules elicit a T-helper cell response which controls the expansion and maturation of selected B cells (i.e. antigen-specific antibodies) and activation of macrophages.
A critical requirement of the immune system is the ability to differentiate between “self” and “non-self” (i.e. foreign) antigens. This discrimination is required to enable the immune system to mount a response to invading foreign pathogens whilst maintaining tolerance to self-proteins and thereby preventing damage to normal tissues. An autoimmune disease results when self-tolerance breaks down allowing the immune system to react against self-tissues such as the joints in rheumatoid arthritis. It is thought that the maintenance of tolerance and thus avoidance of autoimmune disease is critically dependent on the function of MHC molecules.
The observation that many autoimmune diseases are linked to the inheritance of particular MHC alleles suggests a key role for MHC molecules in the pathogenesis of autoimmune disease. For instance multiple sclerosis is linked to the inheritance of HLA-DR2, insulin dependent diabetes mellitus to HLA-DR3 and/or HLA-DR4 and Hashimoto's thyroiditis to HLA-DR5. In particular, an especially strong association exists between predisposition to development of the chronic inflammatory joint disease rheumatoid arthritis and the inheritance of HLA-DR4Dw4 and/or HLA-DR4wl4 and/or HLA-DR1. It is thought that the autoimmune disease associated MHC molecules bind to certain self-antigens and present them to T cells thus stimulating an autoimmune response. Other peptides which can bind to the autoimmune associated MHC molecules and/or either prevent the binding or displace already bound self-antigens and/or which inhibit T cell activation (especially the activity of pathogenic T-cells (e.g. Th 1 cells)) and/or which increase the activity of protective T-cells (e.g. Th 2 cells) or peptides which interact with MHC molecules by an alternative mechanism of action so as to prevent or modify stimulation of an autoimmune response mediated via said MHC molecules, may specifically suppress an autoimmune response.
An agent of this kind would offer therapy for the autoimmune disease whilst avoiding general suppression of the immune system, thus limiting deleterious side-effects. This kind of profile would have significant advantages over current therapy for diseases such as rheumatoid arthritis. It is contemporary practice to treat rheumatoid arthritis initially with symptom relief agents such as NSAIDs, which do not have anv beneficial effect on disease progression and are often associated with unwanted side-effects. Treatment of more severe disease relies on the use of the so-called second-line agents. Often these are general cytotoxic compounds which are of limited efficacy and can cause severe toxicity problems. A rationally based, disease modifying agent, without associated non-specific cytotoxicity, would therefore offer significant benefits in the treatment of rheumatoid arthritis.
Peptides are disclosed in International Patent Application, Publication No's WO 92/02543, WO 93/05011 and WO 95/07707 which bind to MHC molecules and inhibit T-cell activation.
Although a number of peptides have been discovered which inhibit HLA-DR restricted T cell activation by binding to HLA-DR molecules, there is a continuing need for alternative compounds which bind to such molecules and/or either prevent the binding of self antigens or displace already bound self-antigens and/or inhibit T cell activation and/or increase the activity of protective T-cells, or which interact with MHC molecules by an alternative mechanism of action, so as to prevent or modify stimulation of an autoimmune response that cause a disease or condition referred to above.
We have discovered that the peptides of the present invention (set out below) surprisingly possess such pharmacologically useful properties and this is a basis for the present invention.
According to one aspect of the invention there is provided a peptide of the formula I (set out hereinafter)
wherein
either AA
3
together with AA
4
, or AA
4
together with AA
5
, or AA
6
together with AA
7
form a group of the formula II (set out hereinafter) in which Ra is selected from hydrogen and (1-4C)alkyl, and the remainder of AA
1
, AA
2
, AA
3
, AA
4
, AA
5
, AA
6
, AA
7
and AA
8
are L-amino acid residues;
P is a hydrophobic residue, and
Q is OH, NH
2
or NRcRd wherein Re is selected from (1-4C)alkyl, 2-carbamoylcyclopentyl, 2-pyridylmethyl, 4-carbamoylcyclohexyl, 4-carbamoylcyclohexylmethyl 3-carbamoylphenyl, 4-carbamoylphenyl, 4-(carbamoylmcthyl)phenyl, 4-(carboxymethyl)phenyl, 2-morpholinoethyl and a group of the formula —A
1
—G
1
in which A
1
is (3-7C)alkylene or
A
1
is selected from
(1) a group of the formula -A
2
-B
2
- in which A
2
is p-phenylene or 1,4-cyclohexylene and B
2
is (1-4C)alkylcne or A
2
is methylene and B
2
is p-phenylene or 1,4-cyclohexylene; and
(2) a group of the formula -A
3
-B
3
—C
3
- in which A
3
is methylene, B
3
is p-phenylene or 1,4-cyclohexylene and C
3
is (1-3C)alkylene; and
G
1
is a group of the formula —N═C[N(Rp)
2
]
2
in which each Rp is independently selected from hydrogen, methyl, ethyl and propyl; and Rd is hydrogen or (1-4C)alkyl; or
Q is 1-piperazinyl, 4-methyl-1-piperazinyl, 4-amidino-1-piperazinyl, 4-(2-(2-hydroxyethoxy)ethyl)-1-piperazinyl, 1-piperidyl or 4-substituted-1-piperidyl wherein the 4-substitutent is selected from carboxy, carbamoyl, N-(2-aminoethyl)carbamoyl and N-(4-aminobutyl)carbamoyl, or
Q is a sequence of 1 to 6 amino acids or an amide thereof; or a pharmaceutically acceptable salt thereof.
It is to be understood that an amino acid of Q may independently have the D- or L-stereochemistry. Furthermore, when Q is defined as hydroxy (OH), this will be understood to be the hydroxy group of the C-terminal amino acid of AA
8
. Similarly where Q is defined as NH
2
, NRcRd, piperazinyl, piperidyl, etc., this means that the hydroxy group of the C-terminal amino acid AA
8
is replaced by such a group. It is also to be understood that where an amino acid is referred to this means an alpha-amino acid. It is also to be understood that when an L-amino acid is referred to this also includes amino acids such as Gly, 2,2-diethylGly. aza-alanine and aza-glycine which have no chiral carbon atom. It is further to be understood that generic terms such as “alkyl” include both straight and branched chain variants when the carbon numbers permit. The same convention applies to other radicals.
It is well known in the art that compounds having a chiral centre may exist in the form of a racemate (or a mixture of diastereoisomers where there is more than one chiral centre) or as an optically active enantiomer or diastercoisomer. It is also well known in the art that a particular biological activity associated with a racemic or diastereomeric mixture may result largely or solely from a single optically active isomer. It will therefore be understood that the invention concerns any form of a peptide of

Affiliated with

Also associated with

Rating

Inhibitors of peptide binding to MHC class II proteins does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Inhibitors of peptide binding to MHC class II proteins, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibitors of peptide binding to MHC class II proteins will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2591686