261
bicyclic/tricyclic pyrrolopyrimidinone and peptidyl 2,2-difluoro-4-phenylbutyl
ketone (Milligan et al. 1995; Okamoto et al. 1999; Semple et al. 1998). The nonpeptidyl ICE inhibitors were synthesized from a range of chemical backbones including
pyridone aldehydes, phenylalkyl ketones, and activated ketones (Randle et al. 2001).
A series of pyridazine derivatives possess ICE inhibitory action. Inhibition of ICE
is thus regarded as a potential approach for the treatment of inflammation and arthritis. Fused bicyclic peptidomimetic compounds were synthesized as potent IL1β
converting enzyme inhibitors (Soper et al. 2006). Similarly, many synthetic ICE
inhibitors were developed including unsaturated caprolactams, pyrrolopyrimidinones, pyridone, ICEBERG, sulfonamide derivatives, etc. (Harter et al. 2004;
Wagner and Laufer 2006). Several of these are presently validated in in vivo murine
models for sepsis and polyarthritis. Inhibition of IL-1β and IL-18 production by ICE
inhibitors is a promising strategy in managing many inflammatory diseases.
10.7.6.5 Chemokine Inhibitors
Chemokines play an important role in leukocyte infiltration. Their deregulation is
associated with the development and pathophysiology of many inflammatory diseases. The critical role of chemokines in the pathophysiology of many autoimmune
diseases and in metastasis and progression of many cancer types is well established.
Therefore, chemokines and their receptors could serve as vital targets for antiinflammatory therapies. Broad-spectrum chemokine inhibitors are regarded as better choice because of the complexity and redundancy of chemokine system (Castro
Villegas Mdel et al. 2012; D’Ambrosio et al. 2003; Donnelly and Barnes 2006;
Feldmann and Maini 2001; Hampel et al. 2013). Chemokine receptor antagonists
are recently recognized as anti-inflammatory agents against autoimmune diseases
and are under clinical trials. Several CCR1 antagonists were found as potential antiinflammatory and immunosuppressive agents. CCR1 receptors are found to be associated with the progression of many inflammatory disorders (rheumatoid arthritis,
multiple sclerosis) and organ transplant rejection. BX-471 Berlex is a nonpeptide
CCR1 receptor antagonist developed for the treatment of autoimmune diseases
(Elices 2002). CCR2 is another class of chemokine receptors with potential implications in the pathological development of multiple therapeutic agents against autoimmune diseases, atherosclerosis, pain, and metabolic diseases. Maraviroc is a
CCR5 antagonist approved by FDA to prevent HIV infection, and is now acclaimed
for its role as an immune system modulator in autoimmune disorders (Capetti et al.
2010; Francisci et al. 2014). However, clinical trials with single chemokine receptors were not found effective for chronic inflammatory diseases. Thus multitargeting inhibitors have been developed. TAK-779 is a small-molecule antagonist
developed against mouse CCR2, CCR5, and CXCR3. Scheme 527123, another
CXCR2 receptor inhibitor which is chemically derived from 3,4-diaminocyclobut3-ene-1,2-dione, is under clinical evaluation (Russo et al. 2014). CXCR4 antagonist
is the second drug approved by FDA and is employed to mobilize hematopoietic
stem cells. CCR9 inhibitor for treating Crohn’s disease is in phase III clinical trial
(Proudfoot et al. 2010). These are some of the chemokine receptor antagonists
developed for clinical applications.
10 Anti-inflammatory Molecules: Immune System Mediators
bicyclic/tricyclic pyrrolopyrimidinone and peptidyl 2,2-difluoro-4-phenylbutyl
ketone (Milligan et al. 1995; Okamoto et al. 1999; Semple et al. 1998). The nonpeptidyl ICE inhibitors were synthesized from a range of chemical backbones including
pyridone aldehydes, phenylalkyl ketones, and activated ketones (Randle et al. 2001).
A series of pyridazine derivatives possess ICE inhibitory action. Inhibition of ICE
is thus regarded as a potential approach for the treatment of inflammation and arthritis. Fused bicyclic peptidomimetic compounds were synthesized as potent IL1β
converting enzyme inhibitors (Soper et al. 2006). Similarly, many synthetic ICE
inhibitors were developed including unsaturated caprolactams, pyrrolopyrimidinones, pyridone, ICEBERG, sulfonamide derivatives, etc. (Harter et al. 2004;
Wagner and Laufer 2006). Several of these are presently validated in in vivo murine
models for sepsis and polyarthritis. Inhibition of IL-1β and IL-18 production by ICE
inhibitors is a promising strategy in managing many inflammatory diseases.
10.7.6.5 Chemokine Inhibitors
Chemokines play an important role in leukocyte infiltration. Their deregulation is
associated with the development and pathophysiology of many inflammatory diseases. The critical role of chemokines in the pathophysiology of many autoimmune
diseases and in metastasis and progression of many cancer types is well established.
Therefore, chemokines and their receptors could serve as vital targets for antiinflammatory therapies. Broad-spectrum chemokine inhibitors are regarded as better choice because of the complexity and redundancy of chemokine system (Castro
Villegas Mdel et al. 2012; D’Ambrosio et al. 2003; Donnelly and Barnes 2006;
Feldmann and Maini 2001; Hampel et al. 2013). Chemokine receptor antagonists
are recently recognized as anti-inflammatory agents against autoimmune diseases
and are under clinical trials. Several CCR1 antagonists were found as potential antiinflammatory and immunosuppressive agents. CCR1 receptors are found to be associated with the progression of many inflammatory disorders (rheumatoid arthritis,
multiple sclerosis) and organ transplant rejection. BX-471 Berlex is a nonpeptide
CCR1 receptor antagonist developed for the treatment of autoimmune diseases
(Elices 2002). CCR2 is another class of chemokine receptors with potential implications in the pathological development of multiple therapeutic agents against autoimmune diseases, atherosclerosis, pain, and metabolic diseases. Maraviroc is a
CCR5 antagonist approved by FDA to prevent HIV infection, and is now acclaimed
for its role as an immune system modulator in autoimmune disorders (Capetti et al.
2010; Francisci et al. 2014). However, clinical trials with single chemokine receptors were not found effective for chronic inflammatory diseases. Thus multitargeting inhibitors have been developed. TAK-779 is a small-molecule antagonist
developed against mouse CCR2, CCR5, and CXCR3. Scheme 527123, another
CXCR2 receptor inhibitor which is chemically derived from 3,4-diaminocyclobut3-ene-1,2-dione, is under clinical evaluation (Russo et al. 2014). CXCR4 antagonist
is the second drug approved by FDA and is employed to mobilize hematopoietic
stem cells. CCR9 inhibitor for treating Crohn’s disease is in phase III clinical trial
(Proudfoot et al. 2010). These are some of the chemokine receptor antagonists
developed for clinical applications.
10 Anti-inflammatory Molecules: Immune System Mediators