Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-29
2003-12-30
Huang, Evelyn Mei (Department: 1628)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S303000, C514S234200, C514S252110, C514S218000, C540S575000, C544S127000, C544S121000, C544S362000, C544S357000, C546S120000
Reexamination Certificate
active
06670364
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to chemical compounds that are antagonists of MCP-1 function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn's disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection, to pharmaceutical compositions comprising these compounds, to uses of these compounds and compositions especially in the prevention or treatment of such diseases, to methods of treatment employing these compounds and compositions, and to processes for preparing these compounds.
BACKGROUND OF THE INVENTION
Chemokines: Structure and Function
The migration of leukocytes from blood vessels into diseased tissues is an important process in the initiation of normal inflammatory responses to certain stimuli or insults to the immune system. However, this process is also involved in the onset and progression of life-threatening inflammatory and autoimmune diseases; blocking leukocyte recruitment in these disease states, therefore, can be an effective therapeutic strategy.
The mechanism by which leukocytes leave the bloodstream and accumulate at inflammatory sites involves three distinct steps: (1) rolling, (2) arrest and firm adhesion, and (3) transendothelial migration [Springer,
Nature
346:425-433 (1990); Lawrence and Springer,
Cell
65:859-873 (1991); Butcher,
Cell
67:1033-1036 (1991)]. The second step is mediated at the molecular level by chemoattractant receptors on the surface of leukocytes which bind chemoattractant cytokines secreted by proinflammatory cells at the site of damage or infection. Receptor binding activates leukocytes, increases their adhesiveness to the endothelium, and promotes their transmigration into the affected tissue, where they can secrete inflammatory and chemoattractant cytokines and degradative proteases that act on the subendothelial matrix, facilitating the migration of additional leukocytes to the site of injury.
The chemoattractant cytokines, collectively known as “chemokines,” are a large family of low molecular weight (8 to 10 kD) proteins that share the ability to stimulate directed cell migration (“chemotaxis”) [Schall,
Cytokine
3:165-183 (1991); Murphy,
Rev Immun
12:593-633 (1994)].
Chemokines are characterized by the presence of four conserved cysteine residues and are grouped into two main subfamilies based on whether the two amino-terminal cysteines are separated by one amino acid (CXC subfamily, also known as &agr;-chemokines) or immediately adjacent to each other (CC subfamily, also referred to as &bgr;-chemokines) [Baggiolini et al.,
Adv Immunol
55:97-179 (1994); Baggiolini et al.,
Annu Rev Immunol
15:675-705 (1997); Deng et al.,
Nature
381:661-666 (1996); Luster,
New Engl J Med
338:436445 (1998); Saunders and Tarby,
Drug Discovery Today
4:80-92 (1999)].
The chemokines of the CXC subfamily, represented by IL-8, are produced by a wide range of cells and act predominantly on neutrophils as mediators of acute inflammation. The CC chemokines, which include MCP-1, RANTES, MIP-1&agr;, and MIP-1&bgr;, are also produced by a variety of cells, but these molecules act mainly on monocytes and lymphocytes in chronic inflammation.
Like many cytokines and growth factors, chemokines utilize both high and low affinity interactions to elicit full biological activity. Studies performed with labeled ligands have identified chemokine binding sites (“receptors”) on the surface of neutrophils, monocytes, T cells, and eosinophils with affinities in the 500 pM to 10 nM range [Kelvin et al.,
J Leukoc Biol
54:604-612 (1993); Murphy,
Annu Rev Immunol
12:593-633 (1994); Raport et al.,
J Leukoc Biol
59:18-23 (1996); Premack and Schall,
Nature
Med 2:1174-1178 (1996)]. The cloning of these receptors has revealed that cell surface high-affinity chemokine receptors belong to the seven transmembrane (“serpentine”) G-protein-coupled receptor (GPCR) superfamily.
Chemokine receptors are expressed on different cell types, including non-leukocyte cells. Some receptors are restricted to certain cells (e.g., the CXCR1 receptor is predominantly restricted to neutrophils), whereas others are more widely expressed (e.g., the CCR2 receptor is expressed on monocytes, T cells, natural killer cells, dendritic cells, and basophils).
Given that at least twice as many chemokines have been reported to date as there are receptors, there is a high degree of redundancy in the ligands and, not surprisingly, most chemokine receptors are rather promiscuous with regard to their binding partners. For example, both MIP-1a and RANTES bind to the CCR1 and CCR4 receptors, while MCP-1 binds to the CCR2 and CCR4 receptors. Although most chemokines receptors bind more than one chemokine, CC receptors bind only CC chemokines, and CXC receptors bind only CXC chemokines. This ligand-receptor restriction may be related to the structural differences between CC and CXC chemokines, which have similar primary, secondary, and tertiary structures, but different quaternary structures [Lodi et al.,
Science
263:1762-1767 (1994)].
The binding of chemokines to their serpentine receptors is transduced into a variety of biochemical and physiological changes, including inhibition of cAMP synthesis, stimulation of cytosolic calcium influx, upregulation or activation of adhesion proteins, receptor desensitization and internalization, and cytoskeletal rearrangements leading to chemotaxis [Vaddi et al.,
J Immunol
153:4721-4732 (1994); Szabo et al.,
Eur J Immunol
27:1061-1068 (1997); Campbell et al.,
Science
279:381-384 (1998); Aragay et al.,
Proc Natl Acad Sci USA
95:2985-2990 (1998); Franci et al., J Immunol 157:5606-5612 (1996); Aramori et al.,
EMBO J
16:4606-4616 (1997); Haribabu et al.,
J Biol Chem
272:28726-28731 (1997); Newton et al.,
Methods Enzymol
287:174-186 (1997)]. In the case of macrophages and neutrophils, chemokine binding also triggers cellular activation, resulting in lysozomal enzyme release and generation of toxic products from the respiratory burst [Newton et al.,
Methods Enzymol
287:174-186 (1997); Zachariae et al.,
J Exp Med
171:2177-2182 (1990); Vaddi et al.,
J Leukocyte Biol
55:756-762 (1994)]. The molecular details of the chemokine-receptor interactions responsible for inducing signal transduction, as well as the specific pathways that link binding to the above-mentioned physiological changes, are still being elucidated. Notwithstanding the complexity of these events, it has been shown that in the case of the MCP-1/CCR2 interaction, specific molecular features of MCP-1 can induce different conformations in CCR2 that are coupled to separate post-receptor pathways [Jarnagin et al.,
Biochemistry
38:16167-16177 (1999)]. Thus, it should be possible to identify ligands that inhibit chemotaxis without affecting other signaling events.
In addition to their high-affinity seven transmembrane GPCRs, chemokines of both subfamilies bind to various extracellular matrix proteins such as the glycosaminoglycans (GAGs) heparin, chondroitin sulfate, heparan sulfate, and dermatan sulfate with affinities in the middle nanomolar to millimolar range. These low-affinity chemokine-GAG interactions are believed to be critical not only for conformational activation of the ligands and presentation to their high-affinity serpentine receptors, but also for the induction of stable chemokine gradients that may function to stimulate haptotaxis (i.e., the migration of specific cell subtypes in response to a ligand gradient that is affixed upon the surface of endothelial cells or embedded within the extracellular matrix) [Witt and Lander,
Curr Biol
4:394-400 (1994); Rot,
Eur J Immunol
23:303-306 (1993); Webb et al.,
Proc Natl Acad Sci USA
90:7158-7162 (1993); Tanaka et al,
Nature
361:79
Anuskiewicz Steven E.
Inagaki Hideaki
Ishiwata Yoshiro
Jomori Takahito
Kakigami Takuji
Heller Ehrman White & McAuliffe LLP
Telik, Inc.
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