Treatment of Transplantation Rejection and Multiple Sclerosis

7.31 Treatment of Transplantation Rejection and Multiple Sclerosis J S Skotnicki, Wyeth Research, Pearl River, NY, USA D M Huryn, University of Pennsylvania, Philadelphia, PA, USA & 2007 Elsevier Ltd. All Rights Reserved. 7.31.1

Introduction

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7.31.2

Transplantation Rejection

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7.31.2.1

Background

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7.31.2.2

Therapeutic Need

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7.31.2.3

Current Treatment Options

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7.31.2.3.1 7.31.2.3.2 7.31.2.3.3 7.31.2.3.4 7.31.2.3.5 7.31.2.3.6 7.31.2.3.7

Calcineurin inhibitors mTOR inhibitors Inhibitors of nucleotide synthesis Statins Chemokine receptor antagonists Lysophospholipid receptor agonists Tyrosine kinase inhibitors

7.31.2.4

Emerging Research Areas

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7.31.2.5

Summary

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7.31.3

Multiple Sclerosis

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7.31.3.1

Background

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7.31.3.2

Disease Basis

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7.31.3.3

Experimental Disease Models

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7.31.3.4

Current Treatment Options

924 924 924 924 925 925 926 926 926 928 928 928 928

7.31.3.4.1 7.31.3.4.2 7.31.3.4.3 7.31.3.4.4 7.31.3.4.5 7.31.3.4.6 7.31.3.4.7 7.31.3.4.8 7.31.3.4.9 7.31.3.4.10 7.31.3.4.11 7.31.3.4.12

Interferon beta Glatiramer acetate Corticosteroids Azathioprine Methotrexate Cyclophosphamide Mitoxantrone Anti-VLA therapies Intravenous immunoglobulins Cyclosporin Statins Steroid hormones

7.31.3.5

Emerging Research Areas

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7.31.3.6

Summary

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7.31.4

Future Considerations

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References

7.31.1

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Introduction

The immune system is critical in the regulation of many essential functions. Disruption or aberration of these processes is manifested in a number of autoimmune diseases1 including rheumatoid arthritis (RA), multiple sclerosis, inflammatory bowel disease (IBD), cystic fibrosis (CF), type 1 diabetes, systemic lupus erythematosus (SLE), and

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Treatment of Transplantation Rejection and Multiple Sclerosis

asthma. Additionally, the activated immune response is intrinsically involved in transplantation rejection. Accordingly, modulation of the immune system at one or more junctures in the cascade provides an inviting target for therapy. However, due to the importance and complexity in maintaining a responsive immune system, absolute immunosuppression is not a viable option as a therapeutic strategy. Nonetheless, in debilitating diseases and where productive alternatives are not feasible, attenuation of immune processes is an effective strategy. Because of the commonality of mechanistic principles, therapeutic strategies for the treatment of specific autoimmune diseases are often extended beyond the original target. Compound or compound class optimization by the tenets of medicinal chemistry and pharmacology are developed to yield lead compounds for the original target; further analyses and creative thought elucidate that these lead compounds exhibit properties that are superior or appropriate for other pathologies. Thus, significant therapeutic advances have been made without fidelity to a sole target or malady. Based on space considerations and since many of the aforementioned diseases are covered elsewhere in this compendium, this chapter will focus on two of these treatment modalities, transplantation rejection and multiple sclerosis. In both cases, there are examples of approved treatments and potential treatments, and in numerous examples these drugs or drug candidates have multiple mechanisms. In each case, there are examples of the drug and treatment preceding the mechanistic understanding and thus the drugs provided fundamental tools to explore the science. With this surge in understanding, novel molecular targets and newer agents to affect the immune response have been identified. Described within is the focus on important agents for the prevention of rejection in transplantation and treatment of multiple sclerosis regardless of pharmacological ancestry.

7.31.2 7.31.2.1

Transplantation Rejection Background

For the treatment of end-stage organ failure of the kidneys, lung, heart, liver, pancreas, inter alia, a standard and effective approach involves organ transplantation. This approach is direct in concept to replace the diseased organ with the ultimate resumption in function and health. In addition to a variety of concerns and factors associated with the surgical process, a fundamental issue is allograft rejection. The immune system employs a complicated and interconnected array of macromolecules to provide a matrix of complementary and compensatory feedback mechanisms. In this way, the immune system is engineered to serve as the primary guardian of the body to foreign invasion. By this capacity for the body to recognize and address the difference between self and alien, the transplanted organ is susceptible to self-defense in the form of rejection.

7.31.2.2

Therapeutic Need

An approach to address graft rejection is to modulate or suppress the immune system. From the early stages of transplantation research and therapy, scientists have developed and tested hypotheses to affect the correct balance between prevention of rejection and untoward immunosuppressive effects using agents that inhibit one or more components of the immune response. As the basic and clinical research evolved, improvements have been noted and, importantly, the understanding of these complex issues has provided new opportunities for intervention. The tactics employed for the use of immunosuppressive drugs involve therapies related to induction, maintenance, and reversal of rejection. Recent reviews concerning the identification and characterization of immunosuppressants for use in the control of transplantation rejection have appeared.2–12 Nonetheless, some critical problems attendant to molecular intrusion in the immune system are not anticipated and remain unsolved. Immunosuppressive agents often possess inherent drug toxicity to the transplanted organs (e.g., kidney) or display other pathologies, including nephrotoxicity, hepatotoxicity, neurotoxicity, cardiovascular liabilities, and gastrointestinal complications. These are often characterized by very tight therapeutic indices requiring substantial toxicodynamic dose monitoring. Another inherent attribute in the strategy is the possibility of nonspecific immunosuppression, wherein infection and malignancy are significant therapeutic compromises. General reviews concerning side effects have been published.13–18 The widely used agents for the prevention of transplantation rejection fall into a number of mechanistic categories. Some convenient characterizations are protein therapeutics, antimetabolites, glucocorticoids, inhibitors of calcineurin, mTOR, nucleotide synthesis, specific tyrosine kinases 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and G protein-coupled receptor (GPCR) antagonists. Members of each mechanistic class possess specific therapeutic advantages but also carry potential for side effects.

Treatment of Transplantation Rejection and Multiple Sclerosis

Careful examination of this dichotomy and continued experimentation have been used for therapeutic optimization. Combination therapy offers opportunities for systematic discrimination of mechanism-based side effects. Often times the effects for each drug are additive to allow regulation of dose of individual drugs. In some instances, the effects are synergistic taking advantage of upstream or downstream interruptions in a particular immune system cascade. Individual protocols take into account several diagnostic attributes (organ system, characteristics of the patient, other pathology, other pharmacology). These therapeutic regimens are complex.

7.31.2.3

Current Treatment Options

Herein are depicted select compounds used to prevent transplantation rejection. The diversity of both the molecular targets and the structures of the agents are noteworthy. Details of the clinical or preclinical attributes are beyond the scope of this chapter and are discussed in the publications listed in the References. Protein approaches19–21 and glucocorticoids22–26 (see Section 7.31.3.4.3) have been thoroughly reviewed and will not be considered further.

7.31.2.3.1 Calcineurin inhibitors Cyclosporin (1)27–30 is a cyclic peptide and a prominent immunosuppressive agent approved for use in organ transplantation. It forms a molecular complex with cyclophilin and this complex blocks calcineurin with resulting inhibition of T cell proliferation via inhibition of interleukin-2 (IL2) production. Neoral is an improved microemulsion form of 1. A semisynthetic derivative of cyclosporin, ISAtx-247, is reported in development for a number of autoimmune diseases.31 Tacrolimus (2)32–36 is a macrolide antibiotic with immunosuppressive activity and is structurally unrelated to cyclosporin. Tacrolimus forms a molecular complex with a distinct immunophilin, FKBP12, and this complex also binds calcineurin, but with greater molar potency than the cyclosporin–cyclophilin complex. The blocking of calcineurin activation is one basis for the observed toxicities of these molecules.

OH

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7.31.2.3.2 mTOR inhibitors Sirolimus (rapamycin, 3)37–41 is a macrolide antibiotic as well as an important immunosuppressive agent, first approved for use in kidney transplantation in 1999. Though sharing some structural similarities with tacrolimus, sirolimus interferes at a different stage of the T cell activation cascade yielding a unique immunosuppressive mechanism. Sirolimus likewise binds to FKBP12, and this complex in turn blocks mTOR resulting in the arrest of cell-cycle progression at the G1/S phase. Because of this distinct mechanism, sirolimus is able to act synergistically with cyclosporin. Everolimus (4),42,43 an ether analog of sirolimus that operates by the same mechanism, is an effective immunosuppressant. Early and extensive mechanistic studies using cyclosporin, tacrolimus, and sirolomus as pharmacology probes contributed significantly to the understanding of intracellular signal transduction pathways.44–49

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Treatment of Transplantation Rejection and Multiple Sclerosis

OH

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7.31.2.3.3 Inhibitors of nucleotide synthesis Mycophenolate mofetil (5),50–54 an ester prodrug of mycophenolic acid, is a noncompetitive inhibitor of inosine 50 -monophosphate dehydrogenase, IMPDH. By this activity, mycophenolic acid blocks de novo synthesis of guanosine nucleotides, thus inhibiting lymphocyte proliferation and cell-mediated immune responses. Following solution of the structure of IMPDH, other inhibitors such as VX-497 (6)55,56 were identified via structure-based design. O O

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Leflunomide (7)57,58 is an inhibitor of dihydroorotate dehydrogenase (DHODH). It suppresses de novo biosynthesis of pyrimidines, blocking the proliferation of lymphocytes. Leflunomide has been approved for RA and has limited use in transplantation due in part to its long t1/2 in humans (15 days). FK-778 (8)59,60 is a structurally related, newer generation DHODH inhibitor that exhibits more favorable pharmacokinetic properties. N H3C H N

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8 FK-778

7.31.2.3.4 Statins The statins, exemplified by pravastatin (9) are inhibitors of HMG-CoA.61–63 These are used clinically for lipid-lowering capacity, but have also been shown to have anti-inflammatory and immunomodulating properties. The statins have

Treatment of Transplantation Rejection and Multiple Sclerosis

been examined for cardiovascular benefits in the transplantation patient, but there is evidence reported suggesting that statins may be involved in control of rejection.64–66 The statins are further discussed in Section 7.31.3.4.11. HO

OH

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9 Pravastatin

7.31.2.3.5 Chemokine receptor antagonists The chemokines67–69 are a family of structurally related proteins that bind to GPCRs, and are intimately involved in the activation and recruitment of leukocytes. They display pleiotropic biological effects and are implicated in a variety of pathological conditions. The multiple chemokine receptor pathways are complex. SAR studies have been challenging and have been directed mainly to autoimmune diseases. Nonetheless, the involvement of specific chemokine receptors in allograft rejection has been discussed.70–74 BX-471 (10),75,76 a potent and selective CCR1 antagonist that is reported to be active in both multiple sclerosis and transplantation models, is a good example. O HN

NH2

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F N HCl

Cl

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10 BX-471

7.31.2.3.6 Lysophospholipid receptor agonists Lysophospholipids are a family of simple phospholipids that signal through GPCRs and are involved in a broad range of biological processes. The potential of lysophospholipid receptors as targets for immunomodulation in transplant therapy has been reviewed.77–79 One member of this family is sphingosine 1-phosphate (S1P), which is involved in lymphocyte development and B and T cell recirculation. FTY720 (11)80–83 is a nonselective sphingosine 1-phosphate receptor (S1P-R) agonist that is in development for kidney transplantation. FTY720 operates via a unique mechanism of action involving the reduction of peripheral lymphocytes by their sequestering to lymph nodes. HO

OH

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7.31.2.3.7 Tyrosine kinase inhibitors The tyrosine receptor kinases are ubiquitous members of a family that are key in signal transduction processes. They are involved in a number of pathways implicated in oncology and inflammation. Lck and JAK3 are members of this

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Treatment of Transplantation Rejection and Multiple Sclerosis

family, expressed on T lymphocytes and involved in T cell receptor signaling. These kinases have been studied as potential targets for the prevention of transplantation rejection. Following SAR optimization, lck inhibitor A-420983 (12)84,85 and JAK-3 inhibitor CP-690,550 (13)86 have been identified and are illustrative of this concept. O

CH3 N

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12 A-420983

7.31.2.4

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13 CP-690,550

Emerging Research Areas

The continued, and hopefully increased, availability of organs for transplantation will encourage further developments in the search for effective and safe therapeutics.7,87–99 Undoubtedly, medicinal chemistry efforts will continue to pursue improved agents that act through proven mechanisms (e.g., mTOR, calcineurin, nucleotide biosynthesis inhibition, etc.) Emerging areas include tolerance induction, whereby the specific immune response to allograft antigens is prevented. Specific approaches to induce tolerance include targeting the costimulatory pathways (e.g., B7/CD28, antiCD52, major histocompatibility complex (MHC) peptides, anti-CD40 ligand), clonal deletion (e.g., T cell depleting antibodies and immunotoxin conjugates, CTLA-4-Ig, targeting Fas, TNF and Trance pathways, bone marrow microchimerism), Toll-like receptors antagonism, and inhibition of the complement cascade. The control of graft-versus-host disease is another promising avenue in the area of transplantation, as is the use of antisense approaches. Finally, pharmacogenomic approaches will allow personalized therapy and therapeutic regimes that are highly specific to the individual patient and the transplanted organ.

7.31.2.5

Summary

Evolution of the science of immunosuppression has provided significant breakthrough achievements in the control of rejection. Cyclosporin, tacrolimus, sirolimus, mycophenolate mofetil, as well as antibody approaches (e.g., OKT-3, basiliximab, daclizumab) are effective, but have limitations. The balance between prevention of organ rejection and intolerable immunosuppressive properties has yet to be achieved universally. Future antirejection drugs will need to optimize the immunosuppressive profile to ensure organ protection at the expense of dose and schedule limited side effects. In this way, toxicity to the organ and/or the patient, and susceptibility to infection and malignancy will be minimized or eliminated.

7.31.3 7.31.3.1

Multiple Sclerosis Background

Multiple sclerosis is considered to be the most common disorder of the CNS, affecting approximately one million people worldwide, primarily women, and often spanning a course of 30–40 years. While its etiology is unknown, multiple sclerosis is believed to result from an autoimmune response that targets components of the CNS. It is a complex disease characterized by heterogeneity – in symptoms, pathology, disease course, and treatment efficacy. Symptoms of multiple sclerosis vary among patients, are usually episodic, and include fatigue, limb weakness, clumsiness, vision disturbances, and bowel and bladder symptoms. Over the long course of the disease, progressive weakening is common, and within 15 years of onset, 50% of patients will develop disabilities severe enough to require assistance in walking.100–102

Treatment of Transplantation Rejection and Multiple Sclerosis

The heterogeneity of the disease has prompted standardized definitions of four subtypes of multiple sclerosis.103 The relapsing-remitting (RRMS) form of the disease is the most common, occurring in about 80% of cases. Disease onset typically occurs during young adulthood (20s–30s), and affects mainly woman (2:1). It is characterized by acute episodes of neurological symptoms, typically developing over days, followed by remission, which is often complete. In 50% of RRMS patients, the disease course changes and neurological deterioration gradually continues with or without relapses. This form of the disease is termed secondary progressive multiple sclerosis (SPMS). Primary progressive multiple sclerosis (PPMS) is a form of the disease that affects approximately 20% of patients. Symptom severity gradually and continuously worsens from disease onset, with an absence of acute attacks. The incidence of PPMS among men and women is similar, and disease onset is typically later (40–60 years) than RRMS. Progressive relapsing multiple sclerosis (PRMS) is an uncommon form of the disease, and is characterized by gradual deterioration of neurological function with acute episodes superimposed.100

7.31.3.2

Disease Basis

While the event that initiates multiple sclerosis is unknown, it has been proposed that T cells recognizing self-antigen, such as myelin, become activated and initiate a proinflammatory response. Cytokines and tumor necrosis factor (TNF) are released, further amplifying the immune response. Immune cells cross the blood–brain barrier (BBB) and enter the CNS, where proinflammatory cytokines and chemokines are released and induce demyelination. Damage to myelin is believed to cause the early symptoms of multiple sclerosis, however, the molecular mechanisms responsible for myelin degradation are under debate. Several scenarios have been suggested including: damage from microglia and macrophages, cytokine- induced injury, direct antibody binding to myelin, and complement-mediated injury. Regardless of the cause, damaged myelin results in axons being exposed, the inefficient or even loss of nerve conductance, and onset of neurological symptoms. Proinflammatory and proimmune mediators, such as cytokines, chemokines, complement and proteases, may do further damage by acting on the exposed axon, resulting in irreversible injury and neurological deterioration. The mechanism by which remission and resolution of symptoms occurs is also poorly understood. Current hypotheses focus on the release of immunosuppressive cytokines and resolution of the inflammatory response and spontaneous re-myelination, redistribution of sodium channels to restore conduction, and the action of oligodendrocyte precursor cells to regenerate myelin.101,102 The observation that multiple sclerosis relapses are noted to occur after viral infection supports a hypothesis of a viral etiology for multiple sclerosis.101 The molecular mimicry theory applied to multiple sclerosis104 suggests that viral peptide sequences mimic sequences in proteins, such as myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), that constitute the myelin sheath. After viral infection, antigen presenting cells (APCs) and activated T cells mistakenly recognize self-antigens in the CNS, leading to their destruction, and ultimately myelin degradation. Evidence supporting an environmental factor as a cause of multiple sclerosis includes a correlation between disease prevalence and geographic location, several examples of ‘clustering’ of cases, and the change in risk after migration. Disease incidence is highest in Northern Europe, the middle part of North America, and southern Australia, with the demarcation line considered to be above 401 latitude. Migration from an area of lower incidence to an area of higher incidence changes an individual’s risk for developing multiple sclerosis, and age at the time of migration appears to affect how the increased risk is manifested. While these epidemiological characteristics suggest that environmental factors play a role in susceptibility to multiple sclerosis, other data confound this theory, and the precise nature of a putative environmental factor is unknown.101 While an environmental cause of multiple sclerosis is intriguing, the role of genetics in susceptibility is unequivocal. Caucasians are twice as likely to be afflicted with multiple sclerosis than other ethnic groups, and women are more likely to develop the disease than men. First-degree relatives of multiple sclerosis patients have a 20–40 times higher risk of developing the disease than the general population. Presence of the HLA-DR2 allele increases the risk of developing multiple sclerosis considerably, and those populations that have a high frequency of this allele have the highest risk of disease development. The progression and severity of the disease may also rely on a genetic component. Despite the strong genetic component to the disease, most cases are sporadic, and defining the specific genes involved and how they are transmitted is still under investigation.101 Owing to the heterogeneous nature of the disease, it has been suggested that multiple sclerosis may in fact be a series of different diseases, resulting from different exposures (pathogenic, environmental, genetic), and having different pathologies.101 The lack of understanding of the initiating events and the specific pathology of the disease make drug discovery efforts in targeting multiple sclerosis particularly difficult.

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Treatment of Transplantation Rejection and Multiple Sclerosis

7.31.3.3

Experimental Disease Models

Experimental autoimmune encephalomyelitis (EAE) is the animal model most commonly used to mimic human multiple sclerosis, and has been a valuable model to study the disease process itself. It is induced in animals, often rodents such as rat or guinea pig, but also primates, by inoculation with a variety of antigens such as MBP, or even whole brain homogenates. Induction by passive transfer of activated myelin-specific T cells is also common. EAE, like multiple sclerosis, is characterized by infiltration of the CNS by CD4 þ T cells and macrophages resulting in damage to myelin, and eventually impaired nerve conductance and paralysis. By the appropriate choice of species, antigen, and protocol, disease progression in EAE can be tailored to mimic either an acute illness or a chronic relapsing form of the disease. While the similarities between multiple sclerosis and EAE, particularly its clinical presentation, pattern of genetic susceptibility, and observed pathology, are strong, some notable differences are observed in the response to specific therapies, with a trend toward effective therapies in EAE being ineffective in multiple sclerosis.100,105,106 Viral models whose pathology mimic human multiple sclerosis have also been used, albeit less frequently. Infection of mice with Theiler’s murine encephalomyelitis virus (TMEV) causes chronic progressive immune-mediated demyelination that can be ameliorated by immunosuppressive treatment.107

7.31.3.4

Current Treatment Options

Application of conventional drug discovery strategies to multiple sclerosis is difficult due to the lack of understanding of the clinico-pathologic events in the disease process. Current treatment strategies primarily rely on reducing and/or ameliorating the putative inappropriate immune response, with few therapies available to repair damage. During relapses, additional therapies are often prescribed. Therapeutic approaches can be broadly divided into drugs that produce immunosuppression and those that modulate the immune system. Neither approach is ideal. Immunosuppressants typically work through a cytotoxic effect on immune cells. These have broad effects, target several different pathways, and are often very effective. Unfortunately, the likelihood of significant toxicity (cardiotoxicity, malignancies, risk of infection) is also high, and this risk must be balanced with the therapeutic benefit. Immunomodulators act through shifting the immune response to an anti-inflammatory response, and are generally perceived to be less toxic, but also may be less effective in a wide range of patients. In reality, many multiple sclerosis drugs appear to work through several different mechanisms producing both immunosuppressive and immunomodulatory effects.102,106 For the purposes of this review, drugs currently approved to treat multiple sclerosis and those approved to treat other disorders, but with potential to treat multiple sclerosis, will be covered in this subsection. Other agents that show promise in early stages of drug discovery or clinical trials will be covered in Section 7.31.3.5.

7.31.3.4.1 Interferon beta Patients with the relapsing–remitting form of multiple sclerosis are frequently treated with interferon beta. Two forms of the recombinant protein are prescribed: interferon b-1a, identical to natural interferon beta; or interferon b-1b, a nonglycosylated form containing a single amino acid substitution. Clinical trials of these agents demonstrated a significant reduction in disease progression as evidenced by MRI.100 Interferon beta acts through a number of different mechanisms in both the CNS and periphery.102 By activating the interferon receptor, its administration is believed to cause a series of events that result in antiproliferative, immunomodulatory, and (perhaps) antiviral effects.102,108 Interferon beta may be most beneficial at the very early stages of disease, but whether it has a significant effect over the course of the disease is unknown.

7.31.3.4.2 Glatiramer acetate Glatiramer acetate is a mixture of copolymers of four amino acids (L-alanine, L-glutamic acid, L-lysine, and L-tyrosine) in specific stoichiometry that ranges in length from 40 to 90 amino acids. The polymers, originally designed to mimic sequences of MBP, are rapidly degraded to the individual amino acids upon administration. In animal models of EAE, glatiramer acetate suppresses disease induced by MBP, as well as PLP and MOG.100,102,108,109 The mechanism by which glatiramer acetate exerts its beneficial effect has been the subject of considerable debate and study. Recent reports describe it acting at different pathways of the immune response, such as blocking MHC, antagonizing T cell receptors, and inducing regulatory T cells.109,110 The broad immune-modulating activity of glatiramer acetate has also shown benefit in other immune disorders, such as IBD, and during graft rejection.109

7.31.3.4.3 Corticosteroids To treat the underlying immune and inflammatory response, corticosteroids (e.g., methylprednisolone, 14) are prescribed to treat acute relapses. Glucocorticosteriod effects are broad based, and involve immunomodulatory as well as

Treatment of Transplantation Rejection and Multiple Sclerosis

anti-inflammatory effects.23–27,108 By reducing the inflammatory events during a relapse, edema is reduced, the leaky blood–brain barrier is restored, and axonal conductance is improved. The mechanism by which these agents work in multiple sclerosis has been recently reviewed.111,112 OH

OH HO O

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14 Methylprednisolone

7.31.3.4.4 Azathioprine Azathioprine (15) is an immunosuppressant, once widely used to treat patients who had undergone organ transplantation and as a second-line therapy for those diagnosed with autoimmune diseases.100,108 Initially, it was believed to act as a prodrug of 6-mercaptopurine (16, Scheme 1), which, through its incorporation into RNA and DNA, targets activation, proliferation, and differentiation of T and B cells. More recent data indicates that azathioprine’s mode of action may be more complex. It is extensively metabolized (although the extent of metabolism varies among patients) to other purine analogs, which themselves may exert immunosuppressant activity. Some have also suggested that the imidazole product 17, generated during the formation of 6-mercaptopurine, is responsible for some of the drug’s biological effects.113 A number of reviews on this topic have appeared.114,115 NO2 N SH N

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7.31.3.4.5 Methotrexate Methotrexate (18) is a viable treatment option for patients with progressive forms of the disease. It inhibits the enzyme dihydrofolate reductase (DHFR), essential for the synthesis of nucleotides, thereby preventing cell proliferation. This inhibition results in broad anti-inflammatory and immunosuppressive effects. Methotrexate is widely used in anticancer therapy, in addition to its use in other autoimmune diseases such as rheumatoid arthritis.100 H2N

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Treatment of Transplantation Rejection and Multiple Sclerosis

7.31.3.4.6 Cyclophosphamide Owing to its considerable side effects, cyclophosphamide (19, Scheme 2) is typically prescribed for patients with severe and rapidly progressing disease. Similar to the sulfur mustard used as a chemical weapon in World War I, it is an alkylating agent with considerable cytotoxic and immunosuppressive effects, most frequently used to treat cancers and autoimmune diseases. Cyclophosphamide’s mechanism of action relies on metabolic activation that first produces aldophosphamide (20), which in turn generates phorphoramide mustard (21) and acrolein (22). Phosphoramide mustard, through an aziridine intermediate, reacts with a number of targets including nucleic acids and enzymes, and displays some selectivity toward lymphocytes, although the reasons behind the selectivity are poorly understood.116 Weiner and Cohen117 have recently reviewed the multiple sclerosis-specific effects of cyclophosphamide.

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7.31.3.4.7 Mitoxantrone By virtue of its inhibition of topoisomerase II, an enzyme essential for DNA/RNA synthesis, mitoxantrone (23) interferes with cell proliferation and promotes cell death.102 It has been used historically as an anticancer agent, and is believed to work by suppressing T and B cells. Recently, it has been suggested that its efficacy in multiple sclerosis is through induction of apoptosis in antigen-presenting cells, and deactivation of macrophages, the cells primarily responsible for demyelination. However, owing to its side effect profile, the drug is most useful in treating patients with very active disease or those refractive to other therapies.102,108,118

7.31.3.4.8 Anti-VLA therapies Natalizumab is a humanized antibody that targets the alpha four subunit of the integrin, alpha-4 beta-1(also known as VLA-4). By targeting this integrin’s interaction with vascular cell adhesion molecule-1 (VCAM-1), natalizumab prevents entry of lymphocytes into the CNS, and is one of the few therapies that targets multiple sclerosis-selective events, rather than general immunosuppression or immunomodulation. After very promising results in EAE models, and in clinical trials, natalizumab was approved to treat patients with RRMS. Soon after its approval, three cases of progressive multifocal leukoencephalopathy, a serious demyelinating disease of viral etiology, were seen in patients, and the drug was voluntarily withdrawn from the market. After additional review, in June 2006 the FDA approved the resumption of marketing based on a restricted distribution program. Recent data from animal models identify the potential for issues, such as the rapid return of paralytic disease after cessation of treatment (rebound) and worsening of disease if the antibody was administered at the peak of relapsing disease. A number of very thorough reviews of this area have appeared.119–122

Treatment of Transplantation Rejection and Multiple Sclerosis

OH

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The initially promising results from antibody studies prompted significant efforts toward the design of nonpeptide, small molecule inhibitors of VLA-4.123,124 While much of the focus of the work has been in the asthma arena, several reports of small molecules, such as 24–26, that exhibit efficacy in EAE models have been reported.125–129 However, the potential for rebound and exacerbation of disease after treatment with VLA-antagonists,130 as well as issues of possible developmental disorders,131,132 raises concerns about the potential of anti-VLA-4 and anti-adhesion therapies in large numbers of multiple sclerosis patients.

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Treatment of Transplantation Rejection and Multiple Sclerosis

7.31.3.4.9 Intravenous immunoglobulins The mechanism by which intravenous immunoglobulins (IVIgs) provide a beneficial effect in multiple sclerosis patients is complex and multifactorial. Effects on the immune system may be mediated through: anti-idiotype interactions; downregulation and/or neutralization of cytokines and complement-mediated effects; and inhibiting Fc receptors. Studies in animal models of multiple sclerosis (TMEV) showed the possibility of IVIgs promoting re-myelination; however, clinical studies have not yet supported those findings, and the treatment remains a valuable second-line therapy for RRMS.133–136

7.31.3.4.10 Cyclosporin Cyclosporin (1) has been used in multiple sclerosis patients based on its potent immunosuppressive effects; however, its significant side effects reduce its utility in this patient population.100 The use of this drug in transplantation is discussed in Section 7.31.2.3.1.

7.31.3.4.11 Statins Statins, currently used as lipid-lowering drugs, have recently been shown to exhibit certain anti-inflammatory and immunomodulatory effects in vitro and in models of EAE. Their mechanism of action in multiple sclerosis patients is not understood, and may involve inhibition of HMG-CoA reductase or direct effects on the immune system. By inhibition of HMG-CoA reductase, statins may prevent posttranslational modifications of key proteins (e.g., Rho) involved in the immune response. Alternatively, statins have recently been reported to antagonize the adhesion molecule LFA-1 through binding to an allosteric site, and thereby preventing adhesion and costimulation of lymphocytes mediated by LFA-1. In a small study in RRMS patients, simvastatin (27) treatment resulted in a significant decrease in the number of new lesions as measured by MRI. The relative safety of this class of drugs and their ease of administration are significant benefits, but whether statins will exacerbate multiple sclerosis symptoms, as some have proposed, and whether they can become a mainstay of multiple sclerosis therapy remains to be determined.61,64,108,137–141 HO

O O

O H O H

27 Simvastatin

7.31.3.4.12 Steroid hormones A number of observations have suggested a beneficial role for steroid hormones in multiple sclerosis patients. While woman are twice as likely as men to be diagnosed with the disease, progression is typically slower in females than in males. Furthermore, during pregnancy multiple sclerosis symptoms and relapses decline significantly, followed by a dramatic increase post-partum. A number of studies in EAE have demonstrated that steroid hormones (e.g., estriol, 28) can delay progression, and in some cases, prevent disease. The mechanism by which estrogens work is unclear and may involve not only effects on the immune system, but also effects on enhancement and promotion of re-myelination. Small clinical trials have shown promising results, and larger studies are underway. The potential of estrogens and selective estrogen receptor modulators (SERMs) in multiple sclerosis has been reviewed.142–144 OH

H H HO

28 Estriol

OH H

Treatment of Transplantation Rejection and Multiple Sclerosis

7.31.3.5

Emerging Research Areas

According to the National Multiple Sclerosis Society,173 over one hundred clinical trials in multiple sclerosis patients were conducted in 2005. Many of the drugs currently in clinical trials were approved for other therapies, and their utility in the multiple sclerosis patient population is being evaluated. In earlier stages of the drug discovery effort are a number of novel approaches (see a recent review by Wiendl and Kieseier 145). For the purpose of this chapter, those describing peptides as antagonists or elicitors of immune responses and new GPCR targets will be highlighted. The unexpected activity of peptide copolymers, such as glatiramer acetate, in modulating an immune response, as well as the relative safety of the drug, has promoted new efforts aimed at identifying other peptides that may act similarly. A number of approaches focus on interfering with the binding of the T cells to the putative multiple sclerosis auto-antigen, MBP. Peptide 15-mers designed to mimic the MBP-85-99 sequence inhibited the binding of MBP-85-99 to HLA-DR2 and were effective in EAE models.146 Similar strategies using constrained cyclic peptides, peptide mimetics,147 and small molecules148 have also been described, and cite preliminary in vitro results. Ideally, drugs working through this mechanism may be more specific, and therefore more effective, than current therapies, without resulting in the broad immunosuppression which produces significant side effects.149 Peptides based on the sequence of MBP have also been used to induce tolerance to EAE, by inducing anergy in specific T cell populations.150 Several different groups have reported the potential of targeting GPCRs as an approach to immune modulation in multiple sclerosis patients. One promising approach involves the exploitation of lysophospholipid GPCR receptors’ role in mediating immunological effects. FTY720 (11) is phosphorylated in vivo, and that molecule acts as a broad agonist at S1P receptors and is effective in EAE models. Current efforts focus on identifying molecules with S1P receptor subtype specificity.77,151–155 Other GPCR targets for small-molecule multiple sclerosis drug discovery include cannabinoid,156–159 histamine,160 and chemokine (see Section 7.31.2.3.5) receptors.161–165 A wide range of other approaches has also been reported, as have molecules with intriguing activities, however, results are very preliminary. These approaches include cytokine (IL2) suppression,166 mimicking the natural immunosuppressive effects of tryptophan catabolites,167 inhibition of potassium channel Kv1.3,168 and targeting transcription factors involved in the immune response.169 This last hypothesis is supported by the findings that glitazones provide an attenuation of symptoms in EAE models. In addition to small-molecule drug discovery efforts, protein therapeutic and vaccine strategies are also being pursued.102,108,118 Promising new strategies to treat multiple sclerosis patients include the use of neurotrophic factors, neuroprotective agents, T cell targeting therapies (e.g., CTLA-4 Ig),170 bone marrow and glial cell transplantation, leukocyte-targeted antibodies, and antisense99 and siRNA approaches.171

7.31.3.6

Summary

The availability of interferon beta and glatiramer acetate has had a profound effect on the treatment of multiple sclerosis patients. While previous therapies involved immunosuppression, typically with cytotoxic agents, these two biological products have a more subtle effect and work by shifting the immune response away from a destructive response to a beneficial one. Despite these advances, preventative therapies, and those that can elicit repair mechanisms, are lacking, as is a cure. Current treatments typically focus on attenuating the immune response and preventing further damage to myelin and axons. Therapeutic strategies to promote re-myelination and repair damage are areas for future advances.172 Furthermore, research on multiple sclerosis-specific targets remains an area ripe for future efforts. Further advances in understanding its etiology, diverse pathophysiology, and disease course are required before significant gains in new therapies for multiple sclerosis can be realized.

7.31.4

Future Considerations

While graft rejection and multiple sclerosis are very different conditions, both rely on an autoimmune response, and treatment requires a delicate balance between modulating the immune system to prevent symptoms, while at the same time maintaining an appropriate immune response. The availability of drugs that suppress the immune system has ushered in a new era in medicine by enabling organ transplants to become a reality. The use of these same agents and others to treat autoimmune diseases such as multiple sclerosis has allowed a greater understanding of these diseases. As advances in understanding the immune response, its role in disease, and its compensatory mechanisms are made, effective, yet safe, approaches to its modulation will be forthcoming, and ultimately more effective and safe treatments will become available to transplant and multiple sclerosis patients.

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Treatment of Transplantation Rejection and Multiple Sclerosis

Biographies

Jerauld S Skotnicki was born in Niagara Falls, NY. He received a BA in Chemistry from the College of the Holy Cross, an MA in Chemistry from Dartmouth College (under Prof G W Gribble), and a PhD from Princeton University (under Prof E C Taylor). Prior to his studies at Princeton, Dr Skotnicki was staff chemist at Lederle Laboratories for 3 years. Following his PhD, he joined the Biochemicals Department at DuPont as Research Chemist. In 1982, Dr Skotnicki joined Wyeth as a Medicinal Chemist at Wyeth Laboratories in Radnor, PA and Wyeth-Ayerst Research in Princeton, NJ, and he became a Director of Medicinal Chemistry at Wyeth in Pearl River, NY. His research experience has been in the areas of immunoinflammatory diseases, infectious diseases, musculoskeletal diseases, oncology, and transplantation. Since 2004, in his current position as Senior Director of Chemical Sciences Interface, Chemical and Screening Sciences at Wyeth he has responsibility for research activities at the junction of discovery and development, as well as management of external alliances in Chemical and Screening Sciences. Dr Skotnicki was the recipient (2004) of the Thomas Alva Edison Patent Award in ‘Emerging Technologies’ for his contributions to the discovery of temsirolimus. He is currently an editor of Inflammation Research and serves as a manuscript reviewer for the Journal of Medicinal Chemistry, Journal of Organic Chemistry, Bioorganic and Medicinal Chemistry Letters, Tetrahedron, Chemistry & Biology, and Medicinal Chemistry. He has served on the Board of Directors of the Inflammation Research Association (2000–04).

Donna M Huryn received her BA degree from Cornell University and her PhD in Organic Chemistry from the University of Pennsylvania. She joined the Chemistry Department at Hoffmann-La Roche and worked in the areas of anticancer, anti-inflammatory, immunonology, and anti-viral agents. In 1993, she moved to Wyeth Research’s Chemical Sciences Department where she led the CNS Medicinal Chemistry Department in projects targeting multiple sclerosis, Alzheimer’s disease, and depression, among others, and then led the Chemical Sciences Interface Department. Dr Huryn is currently Associate Director of the Chemistry Core at the Penn Center for Molecular Discovery (University of Pennsylvania), Scientific Advisor to the University of Pittsburgh Center for Chemical Methodology and Library Design, Senior Scientific Fellow at the Pittsburgh Molecular Library Screening Center, and

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Adjunct Professor of Pharmaceutical Sciences at the University of Pittsburgh. In addition, she is a consultant to several technology and biotech companies. She has served on a number of local and national committees of the American Chemical Society, and is a member of the Editorial Advisory Board of Organic Letters. Dr Huryn was a member of the NIH Medicinal Chemistry Study Section from 1996 to 2000, and is a frequent ad hoc member of the Drug Discovery, Development and Delivery SBIR Study Section.

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Comprehensive Medicinal Chemistry II ISBN (set): 0-08-044513-6 ISBN (Volume 7) 0-08-044520-9; pp. 917–934