Arylamines as inhibitors of chemokine binding to US28

Details Arylamines as inhibitors of chemokine binding to US28 Arylamines as inhibitors of chemokine binding to US28

2002-08-29

2004-11-23

Desai, Rita (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S428000, C514S645000, C548S575000, C548S577000, C564S304000

Reexamination Certificate

active

06821998

ABSTRACT:

BACKGROUND OF THE INVENTION
Cytomegalovirus (CMV) is an important human pathogen and a major opportunist which emerges to cause disease in the immuno-compromised such as AIDS patients, neonates, and individuals who have been given immunosuppressive drugs as part of a transplantation regimen. In these individuals, the consequences of CMV in acute or re-emerging infections can be dire, including retinitis, encephalitis, and pneumocystis, among other pathologies. Furthermore, in immuno-competent hosts, CMV establishes a persistent lifelong infection through which it has been linked to a variety of inflammatory conditions including coronary artery occlusion following heart transplant and atherectomy and restenosis following angioplasty. CMV interacts with leukocytes during acute infection of the host as well as during lifelong latency. As such, leukocytes are important players in CMV-induced disease and have been implicated in the acute phase of infection as vehicles for dissemination of virus and as sites of residence during lifelong latency.
CMV harbors in its genome an open reading frame (ORF), designated US28, which encodes a protein that acts as a functional receptor for certain human and viral chemokines. Upon infection of a cell by CMV, US28 is expressed on the surface of the infected cell and becomes capable of responding to chemokines in the environment. Because the virus on its own is inherently non-motile, and because chemokines and their receptors encoded by human cells are known to regulate the migration of leukocytes and other cells through the body, CMV US28 is thought to be encoded by the virus to facilitate the dissemination of CMV through the body during and after infection. Therefore, agents which block the binding of chemokines to US28 should prove useful in inhibiting viral dissemination during acute or re-emerging CMV infection.
CMV US28 has been shown to bind a variety of human, murine, and virus-encoded CC chemokines in a variety of assay formats. In addition, the CX3C chemokine, Fractalkine, binds with a very high affinity (K
I
~50 pM) to US28. Fractalkine is expressed on certain endothelial cell surfaces and on populations of dendritic cells (DC), and may thus define a portal through which CMV infected cells go from the circulation to the tissue space, as well as find residence in the DC.
Since the US28 receptor is expressed on cytomegalovirus infected cells, and also in view of its ability to bind multiple chemokines, a small molecule inhibitor for this receptor would have significant use as an anti-CMV agent.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides methods for treating or preventing viral dissemination from CMV infection. The methods typically involve administering to a patient an effective formulation of one or more of the compounds of formula I:
wherein Ar is a substituted or unsubstituted 5-14 membered heteroaryl group having from 1 to 5 heteroatoms as ring members, or a substituted or unsubstituted (C
6
-C
14
)aryl group; L is a substituted or unsubstituted linkage having from two to fourteen contiguous chain atoms selected from the group consisting of C, N, O, P and S; and R
1
and R
2
are each independently selected from (C
1
-C
4
)alkyl, wherein the alkyl portions of L, R
1
and R
2
are optionally substituted with from one to four substituents selected from halo, OR′, SR′, S(O
p
R′, and CO
2
R′, in which R′ is H or a (C
1
-C
4
)alkyl group, and the subscript p is 1 or 2; or R
1
and R
2
are optionally combined with the nitrogen atom to which each is attached to form a ring selected from aziridine, azetidine, pyrrolidine, piperidine, imidazoline, piperazine and morpholine, each of the rings being optionally substituted with from one to three substituents selected from (C
1
-C
4
)alkyl, phenyl, phenyl(C
1
-C
4
)alkyl, hydroxy, hydroxy(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy(C
1
-C
4
)alkyl and di(C
1
-C
4
)alkylamino) C
1
-C
4
)alkyl.
In a group of particularly preferred embodiments, the compounds have the formula:
wherein the subscripts m and n are each independently integers from 1 to 2; R
1
and R
2
are as defined above for formula I; and R
3
and R
4
are each independently selected from the group consisting of (C
1
-C
4
)alkyl, or when taken together with the nitrogen atom to which each is attached, form a ring selected from the group consisting of aziridine, azetidine, pyrrolidine, piperidine, imidazoline, piperazine and morpholine, each of the rings being optionally substituted with from one to three substituents selected from (C
1
-C
4
)alkyl, phenyl, phenyl(C
1
-C
4
)alkyl, hydroxy, hydroxy(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy(C
1
-C
4
)alkyl and di(C
1
-C
4
)alkylamino(C
1
-C
4
)alkyl.
Additionally, the invention provides compositions of the above compounds in combination with a pharmaceutically acceptable carrier or excipient.


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