Medicinal Chemistry Cytoprotective And Adsorbent

;NHS03Na

OSOsNa

OSOsNa

NHS03Na ficacy of hyaluronic acid in the treatment of osteoarthritis of the knee and other large joints. In addition to restoring the elasticity and viscosity of the synovial fluid, hyaluronic acid modulates acute and chronic inflammation processes both in animals and human beings (31). Specifically, hyaluronic acid interacts with endogenous receptors such as CD 44, ICAM-1, and RHAMM and may play an important role in controlling a variety of cellular behaviors, such as the migration, adhesion, and activation of pro-inflammatory cells, chondrocyte maturation or differentiation, and matrix synthesis in the cartilage microenvironment (32).

A highly purified, high molecular weight, high viscosity injectable form of hyaluronic acid (Orthovisc) is available to improve joint mobility and range of motion in patients suffering from osteoarthritis of the knee (33) .Or-thovisc is injected into the knee to restore the elasticity and viscosity of the synovial fluid.

2.1.7 Enzyme Replacement. In contrast to all the drugs discussed thus far, carbohydrate enzyme replacement therapeutics is different in that the enzyme drugs are not primarily structurally related to carbohydrates, but play an important role in saccharide or glycoconju-gate processing. Coincidentally, the replacement strategy requires high affinity receptor-mediated uptake and delivery to lysosomes that is regulated by specific oligosaccharide side-chains of these enzymes.

Carbohydrate enzyme replacement therapy is the administration of exogenous enzymes to patients that have defective saccha-ride-processing enzymes that result in an accumulation of harmful metabolic products. Metabolic diseases often have genetic causes and some of these diseases involve saccharide or glycoconjugate metabolites. Two examples are Gaucher's and Fabry's disease.

Gaucher's disease is a glycolipid storage disease and results from genetic mutations that can either slow or prevent the breakdown of certain glycolipids. Patients with Gaucher's disease are born with a deficiency in the enzyme glucocerebrosidase that results harmful quantities of a fatty substance called glucoce-rebroside to accumulate in the spleen, liver, lungs, and bone marrow.

Fabry's disease is an inherited genetic disorder caused by deficient activity of the lysosomal enzyme a-galactosidase A. In patients with Fabry's disease, harmful quantities of globotriaosylceramide accumulate in the kidney, heart, nervous system, and blood vessels.

Imiglucerase is a recombinant form of the enzyme glucocerebrosidase and it is approved to treat type 1 Gaucher's disease. The therapy is highly effective, but it requires a 2-h intravenous infusion as often as three times a week and is expensive.

Agalsidase alfa is a human a-galactosidase A produced by genetic engineering technology in a human cell line. Patients can receive agalsidase alfa every other week in a 40-min intravenous infusion at home rather than in a hospital setting.

Although Table 7.1 does not contain all the new carbohydrate-based drugs introduced into the market in the last decade, it should be representative. The choice of what to include in Table 7.1 is also arguable. Nevertheless, it is impressive that in the last decade, over 20 carbohydrate-based drugs have been approved.

2.2 Therapeutics in Development

In the past decade there has been significant progress in development of carbohydrate-based therapeutics. Also, new methods for the large-scale production of carbohydrates and their analogs are allowing the thorough evaluation of their safety and efficacy in human trials.

Challenges that face the development of carbohydrate-based therapeutics continue to include the need to procure sufficient amounts of complex carbohydrates, which is often difficult and expensive, whether they involve synthesis or isolation from natural sources. Additional challenges include the lowbioavail-ability of orally delivered carbohydrates and the inability of many animal models to provide data relevant to human disease. In contrast to the challenges, advantages in favor of carbohydrate-based therapeutics include low toxic-ity and high structural diversity. This section, like marketed drugs above, is divided by molecular weight and organized into therapeutic classes.

The therapeutic classes are grouped as follows: gastrointestinal system, central nervous

Table 7.1 To Market—Last Decade

Generic Name (Brand Name)

Acarbose (1) (Precose, Glucobay, Prandase) Voglibose (2) (Basen, Glustat) (AO-128) Miglitol (3) (Glyset, EAY

m 1099) Dolsarnate (4) (Flavalfate,

F3616M) Topiramate (5)

(Topamax) Arbekacin (6) (Habekacin) Zanamivir (8) (Relenza)

GG167 Oseltamivir (9) (Tamiflu)

Pneumococcal heptavalent vaccine (Prevnar) Haemophilus b (ActHIB,

OmniHIB) Typhoid Vi (Typhim Vi) Drotrecogin alfa (Xigris) Dalteparin (Fragmin)

Enoxaparine (Lovenox)

Nadroparine

(Fraxiparine) Ardeparin (Normiflo)

Danaparoid (Orgaran)

Fondaparinux (10)

(Arixtra) Hyaluronic acid

(Orthovisc) Imiglucerase (Cerezyme) Agalsidase alfa (Replagal)

Indication Diabetes

Diabetes

Diabetes

Gastric ulceration

Anti-convulsant, anti-epileptic Anti-microbial

Anti-viral

Anti-viral

Conjugate vaccine

Conjugate vaccine

Conjugate vaccine Sepsis

Anti-coagulant, antithrombotic Anti-coagulant Antithrombotic Anti-coagulant, antithrombotic Anti-coagulant, antithrombotic Anti-coagulant;

antithrombotic Anti-coagulant;

antithrombotic Viscoelastic supplement Gaucher's disease Fabry's disease

Company Bayer AG

Takeda and Abbott

Bayer

Faes

Ortho-McNeil,

Johnson & Johnson Meiji Seika

GlaxoSmithKline

Hoffmann-La Roche

Gilead Wyeth

SmithKline Beecham,

Pasteur Merieux Pasteur Merieux

Pharmacia Upjohn Aventis

Sanofi-synthelabo

Wyeth

Organon

Organon and Sanofi-

Synthelabo Anika, Zimmer

Europe Genzyme Transkaryotic Therapies

Approval Country and Year

U.S. in 1995 Japan in 1994 U.S. in 1996 Spain in 2000 U.S. in 1996,1999 Japan in 1997 U.S. in 1999 U.S. in 1999 U.S. in 2000

France in 1996

France in 1986

Europe and Canada in 1998 U.S. in 1994 Europe in 2001

system, infection, cancer, inflammation, and lysosomal storage. The major difference from the marketed drugs is that the diabetes class is not represented. With diabetes, it is not clear why no new mechanism drug is being developed to follow up the success of a-glucosidase inhibition. In place of diabetes, cancer therapeutics is added with a focus on cancer vaccines that are in clinical development.

2.2.1 Gastrointestinal System. Oral cyto-protective agents like dosmalfate (4) have not been followed in development presumably because the mechanism of action is not well understood. In place of cytoprotection in gastrointestinal drug development is motilin antagonism.

Mitemcinal (11) is an agonist of motilin, a peptide hormone that plays a role in the con-

Reactive Red 141 Adsorption

tractile movement of the gastrointestinal tract (34).Mitemcinal (11) is an erythromycin A derivative that is being studied in phase II clinical trials to assess its effect on the recovery cf gastrointestinal motility. Gastrointestinal motor-stimulating activity is a side effect of erythromycin, and other compounds based on erythromycin, such as EM574, are in development (35).

2.2.2 CNS. Because CNS active drugs tend to have appreciable lipid solubility, it is not surprising that a glycolipids-based drug would be in development. What seems to be the problem, however, is glycolipid drug supply.

The development the glycolipid ganglioside GM1, called Sygen (12), for treating Parkinson's disease was reported (36). This complex molecule is currently isolated from natural sources and studies into its large-scale synthesis are underway. A phase II clinical trial for acute spinal cord injured patients was started in 1997. Results from single center studies, as well as efforts in experimental spinal cord injury and stroke, indicated that Sygen (12) promoted improvement in neurological status. However, there were problems. Early forms of the drug were often impure and there were several severe complications from the use of the European version of the drug. Also, higher doses of Sygen (12) were associated with increased risks in that there was a small incidence of allergies and an increase in cholesterol that was related to being on the drug for a period of time (37).

2.2.3 infection. Anti-infective carbohydrate-based therapeutics in development include antibiotics and antivirals. The emergence of multi-drug resistant bacteria has increased the need for new antibiotics or modifications of older antibiotic agents. The modification of known antibiotics may be a productive way to combat multi-drug resistant bacteria.

2.2.2 CNS. Because CNS active drugs tend to have appreciable lipid solubility, it is not

Everninomycin (13), an intravenous antibiotic, was in development for hospitalized patients with resistant gram-positive infections. Phase III clinical studies, however, showed that the balance between efficacy and safety did not justify further development of the product.

Everninomycin (13), although promising, may have been a victim of antibiotic overuse. Another oligosaccharide, avilamycin, which is structurally similar, has been used as a growth promoter for food animals in the European Union. The use of avilarnycin as a growth promoter has created a reservoir of isolates with decreased susceptibility to everninomycin (13)before this antibiotic was finally approved for human use (38).

The total synthesis everninomycin may allow semi-synthetic variants of this antibiotic to be made that are active versus multi-resistant bacteria (39).

Development of the pediatric ear infection drug, NE-1530, was terminated based on a phase II clinical trial data in which NE-1530 showed no significant benefit compared with placebo (40). Another candidate, NE-0080, was being evaluated as a treatment for stomach ulcers and other gastric complaints caused by the bacterium Helicobacterpylori,but after phase I trial indicated the safety (41), no further information became available.

Shiga toxin, which is produced by Shigella dysenteriae, and the homologous Shiga-like toxins (SLTs) of E. coli, can cause serious clinical complications in humans infected by these organisms. The functional toxin receptor on mammalian cells is the glycolipid Gb3 [a-D-Gal(l 4) j3-d-Gal(l 4) j3-d-G1c(1 O-cer-and the high incidence of complications such as acute kidney failure in children correlates with the expression of Gb3 in the pediatric renal glomerulus. Synthetic Gb3 analogs covalently attached to insoluble silica particles can competitively adsorb toxin from the gut and can serve as a starting point for the adsorbent carbohydrate drugs.

Indeed, two orally delivered, carbohydrate-based, silica-linked, gastrointestinal anti-infective therapies were advanced to clinical trials. Synsorb Pk was developed for the treatment of E. coli infections to prevent hemolytic uremic syndrome. The target E. coli variant produces verotoxin, the toxin in "hamburger disease." The other silica-linked oligosaccharide drug, Synsorb Cd, was for the treatment of C. difficile-associated diarrhea. Both compounds were discontinued in development.

Peramivir (14) is a neuraminidase inhibitor that is reported to have both an excellent safety profile and effective against influenza A and B. It is orally active, given in a once-a-day dosage, and can be made into a liquid form, allowing for use by the elderly and young children.

In a clinical challenge study, a clear dose response is seen for the primary endpoint (area under the curve versus viral titer). Doses of peramivir (14) ranging from 100 to 400 mg/ day produced a dose-dependent, virological efficacy response compared with placebo. Peramivir (14) at 400 mg once daily for 5 days results in a highly significant reduction in mean viral titer area under the curve and duration cf viral shedding compared with placebo.

Despite promising early data on activity, further development of SC-48334 (15)(AM)u-tyl-deoxynojirimycin) for HIV infection was discontinued. Trials in AIDS/ARC patients indicated that the drug had no significant effect on p24 antigen levels or CD4 cell counts (42). SC-48334 (15) was not found to be of any ma-

jor benefit in reducing viral load in a phase II trial (43). Although (15) did not find use in HIV, it is being developed under a different name, vevesca, for the treatment of lysosomal storage disease (see Section 2.2.7). This is an example of how understanding the glycobiol-ogy and using this knowledge can be used to discover efficacy in another indication.

Celgosivir (16) demonstrates inhibitory effect on glucosidases and has antiviral activity against HN-1 and against murine leukemia virus. Celgosivir (16) was tested alone or in combination with AZT orally in AIDS patients with CD4+ counts between 100 and 500 cells/

fih. Preliminary efficacy measurements showed good results for one-third of the patients, stable results for one-third, and rather poor results for the other one-third of the patients (44). No further clinical development has been forthcoming with Celgosivir (16).

A prototype vaccine against E. coli 0157 triggered a strong protective response in healthy volunteers (45).Within a week of vaccination, 80% of the 87 volunteers had developed large numbers of antibodies that killed laboratory cultures of E. coli 0157. The response may be rapid enough to protect people once an outbreak has begun, particularly the elderly and young children who are most vulnerable to infection.

The vaccine has two components, a carbohydrate called the 0-specific polysaccharide, which appears on the surface coat of E. coli 0157, and a protein from Pseudomonas aeruginosa, the bacterium that causes pneumonia.

2.2.4 Thrombosis. The enzymatic cleavage at specific sites in heparin could be important for anticoagulation therapeutics. By cleaving heparin, heparinase I inactivates heparin's anticoagulant effects. Neutralase (heparinase I) is being developed as a replacement to protamine that is currently used to reverse the effects of heparin. In contrast to protamine, which binds to heparin to form large macro-molecular complexes, neutralase enzymati-cally breaks heparin into small, mostly inactive, fragments.

Pre-clinical studies indicate that neutralase can also inactivate the anticoagulant effects of the low LMW heparins and the synthetic pentasaccharide fondaparinux (10) (see

Section 2.1.5). Neutralase is able to neutralize these agents because it cleaves the recognition site for anti-thrombin.

OP2000 is an oligosaccharide product derived from heparin with antithrombotic and anti-inflammatory properties and is in development for inflammatory bowel disease (IBD).

IBD is a group of chronic inflammatory disorders of the intestine of unknown cause, often causing recurrent abdominal pain, cramps, diarrhea with or without bleeding, fever, and fatigue. Two forms of IBD are Crohn's disease, which affects the lowest portion of the small intestine, and ulcerative colitis, which results in inflammation of the large intestine.

Clinical observations suggest that IBD may result from increased clotting activity. Investigators have observed evidence of increased clotting in the bowel and other organs during flares of IBD. Clinical pharmacology of hepa-rin in ulcerative colitis support the idea that heparin can safely induce remission in IBD patients. OP2000 is a product of the chemical cleavage of heparin and has the comparatively low molecular weight of 2.5 kDa. OP2000 is a potent anti-clotting agent like other LMW heparins.

2.2.5 Inflammation. Cylexin was studied for preventing reperfusion injury in infants (46). Clinical trials with cylexin were halted based on disappointing results from its ongoing phase II/III clinical trial. Cylexin showed no benefit over placebo in a 138-patient trial for the treatment of reperfusion injury in infants undergoing cardiopulmonary bypass to facilitate the surgical repair of life-threatening heart defects. Until then, cylexin was the most advanced selectin-binding inhibitor.

P-selectin is a major component in the early interaction between platelets and neutrophils, and endothelial cells. in the initial inflammatory response. A major ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1), and this ligand is expressed on the surface of monocyte, lymphocyte, and neutrophil membranes.

PSGL-1 is a 240-kDa homodimer consisting of two 120-kDa polypeptide chains. The structure of functional PSGL-1 includes the sLex oligosaccharide. The PSGL-1 gene en codes a transmembrane polypeptide rich in serine, and threonine residues typical of mucin glycoproteins. The 0-linked glycans displayed by PSGL-1 must have two specific post-translational modifications, a-l,3-fucosy-lation and «-2,3-sialylation, to be active as a counter-receptor for P-selectin. Bonds between P-selectin and PSGL-1 primarily mediate the rolling phase of the adhesion cascade.

A partial form of recombinant human PSGL-1 has been covalently linked to IgG to give rPSGL-Ig (47). This fusion peptide is active as a competitive inhibitor of PSGL-1, and in an animal model, pretreatment with rPSGL-Ig reduces both the thrombo-inflam-and neointimal proliferative responses (48). As an inhibitor of neutrophil-endothelial cell adherence, rPSGL-Ig was in early clinical development for the treatment of ischemia-reperfusion injury.

A double-blind randomized, multi-center placebo-controlled, dose-ranging phase II study on the efficacy and safety of recombinant rPSGL-Ig in patients with acute myocardial infarction (MI) was assessed by positron emission tomography. The trial was negative, and product development has been discontinued for MI.

Inhibiting P-selectin may prevent not only ischemia reperfusion injury but also the subsequent clotting events that can re-occlude a vessel that's just been opened. PSGL-1 binds to a selectin-P subtype on platelet cells, causing red blood cells to stick to leukocytes and create blood clots.

In addition, inhibiting P-selectin may also prove to be useful for stopping the spread of tumors. Metastasizing tumor cells recognize P-selectin on platelets and use them as a protective shield against immune system cells. The development indications for rPSGL-Ig are not only in inflammation but also cancer.

2.2.6 Cancer. The development of carbohydrate-based vaccines designed to activate T-cells targeting of cancer cells has been pursued for some time. The goal of a cancer vaccine is to make the host immune system responsive to antigens characteristic of cancer cells. Several carbohydrate-based therapeutics that have now reached clinical trials seek to estab lish the molecular vaccine design in which a cell surface antigen activates T-cells (49).

Theratope is a cancer vaccine that consists of modified tumor glycopeptide antigens for patients with advanced breast cancer. The antigen is attached to Keyhole Limpet Hemocy-anin (KLH) protein to increase the immune response to the vaccine. The vaccine uses a carbohydrate antigen known as STn, part of a larger antigen, mucin-1, found on breast cancer cells. Theratope is in phase III human trial, which has as an endpoint of increased survival.

Earlier studies in humans provide strong evidence of the development of an anti-tumor T-cell response after immunization with a cancer-associated carbohydrate antigen (50).

The hexasaccharide, globo H, is found on cancer cells and is an antigen for vaccine design. Globo H occurs on cell surface glycoproteins cf breast, prostate, and other epithelial cancers, and the expressed levels of these antigens are magnified in the context of such tumors. Chemists have synthesized globo H, and, as in the case of Theratope, attached it to KLH to augment the antigen's immunogenic-ity (51).

The globo H vaccine is being tested in clinical trials to determine whether it will block the reappearance or progression of cancer. Thus far, in a group of 27 women with meta-static breast cancer, globo H raised blood levels of IgM antibodies. In 16 of these patients, IgM antibodies bound to the cancer cells, and some patients showed evidence of cancer cell death (52).

Similarly, prostate cancer patients who relapsed after surgery or radiation therapy are being treated with the globo H tumor vaccine (53). The vaccine was established as safe and capable of inducing specific antibody response to globo H. More importantly, the immune response to the vaccine based on synthetic globo H-protein conjugate also recognized naturally occurring cancer-derived glycoprotein.

An effective treatment for the deadly skin cancer melanoma is clearly needed. Current best therapy is surgical removal of high-risk melanoma and treatment with Interferon alfa. Melanoma patients have a 50-80% chance of relapse without adjuvant treatment. The GMK vaccine is in development for melanoma and contains the ganglioside GM2 linked to the carrier protein KLH and combined with the adjuvant QS-21.

GMK vaccine is capable of producing a specific immune response against a defined and chemically purified melanoma antigen. Anti-GM2 antibodies in melanoma patients induced by the GMK demonstrate binding to melanoma cells, complement-mediated cytotoxicity, and antibody-dependent cellular cytotoxicity (54).

GMK vaccine was compared with high-dose Interferon alfa 2b in high-risk melanoma patients who had undergone surgery. Inter-feron-treated patients were 50% less likely to experience a return of their disease and 52% less likely to die than were GMK-treated patients (55).

Another vaccine, MGV, is being developed for several other cancer indications, including colorectal, lymphoma, small-cell lung, sarcoma, gastric, and neuroblastoma. The cell surface gangliosides GM2 and GD2 are expressed on several cancers, including melanoma. GM2 is immunogenic, and induction of anti-GM2 antibodies correlates with improved survival in stage III melanoma patients with no evidence of disease after surgery. GD2 is immunogenic when coupled to KLH and mixed with the adjuvant QS21. The development of GMK and MGV cancer vaccines seems to be on hold.

Other carbohydrate-based drugs in development to treat cancer include a sulfated oligosaccharide^ pectin derivative, and an aza-sugar. PI-88 is a sulfated oligosaccharide, GAG mimetic that inhibits growth factors and heparanase produced by tumors and has anti-angiogenic and anti-metastatic properties. In pre-clinical studies, PI-88 retarded the growth of primary tumors by inhibiting angiogenesis, and in a rat model, it showed a dose-dependent inhibition of tumor growth in the BC1 syngeneic rat mammary adenocarcinoma (56). This inhibition is thought to be the result of its ability to inhibit endothelial cell proliferation by preventing basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) from binding to the receptors on endothelial cells. PI-88 also inhibits heparin-ase secreted by a variety of cells, thus prevent ing the degradation of extra-cellular matrix and the release of growth factors.

A multi-center phase II clinical trial to further investigate the efficacy and safety of PI-88 in patients with multiple myeloma was started. The trial will also gather information about PI-88's ability to inhibit the blood vessels formation in tumors.

Carbohydrates have demonstrated an increasing role in tumor biology, with a known correlation between the expression of the ga-lectin 3 receptor and the propensity for metastatic spread in pre-clinical models (57). The carbohydrate GCS-100 is a pectin derivative that binds to the galectin 3 receptor. Pectin is the methylated ester of polygalacturonicacid.

In pre-clinical models, GCS-100 is able to inhibit the metastatic spread of tumor lines to the lung and is able to shrink large tumors. In pre-clinical toxicology studies, the dose limiting effect of GCS-100 is pulmonary insufficiency.

GCS-100 is in phase II clinical trials for pancreatic and colorectal cancer. Phase Ila data in failed metastatic pancreatic and colo-rectal cancer patients warranted proceeding into larger studies.

Oligosaccharide moieties of cell-surface glycoproteins are involved in recognition events associated with cancer metastasis. GD0039 (17), an inhibitor of Golgi a-manno-

sidase II, is used to examine the role of glycan structures in metastasis (58). GD0039 (17) blocks pulmonary colonization by tumor cells and stimulates components of the immune system, such as macrophagesand splenocytes. Furthermore, GD0039 (17) abrogates much of the toxicity of commonly used chemothera-peutic agents in both healthy and tumor-bearing mice. GD0039 (17) is in phase II clinical trials in metastatic renal cancer and 5-FU resistant colorectal cancer.

2.2.7 Lysosomal Storage. Lysosomal storage diseases (LSDs) are genetic errors of metabolism resulting primarily from the absence of an enzyme whose target is a substance to be lowered in cellular tissues. The build-up of these substances causes a loss of function in one or several crucial areas of the body and may result in mental and physical disability, or in most cases, shortened lifespan. A partial list of LSDs includes glycolipidosis disorders, such as Fabry's and Gaucher's diseases (discussed in Section 2.1.7), and mucopolysaccharidosis (MPS), such as MPS I and VT diseases. Both small molecule enzyme inhibitors and large molecule enzyme replacement approaches are being taken to treat LSDs.

OGT-918 (15) (vevesca, AMnityldeoxynojiri-mycin) is in clinical development for the treatment of Gaucher's and Fabry's diseases. OGT 918 is a small molecule drug and as such can be given orally. Analysis of a 6-month study to investigate the potential of OGT 918 treatment in Fabry's patients who had been receiving enzyme therapy (see agalsidase alfa, Section 2.1.7) indicates that the patients were successfully maintained on oral therapy alone during the study period.

It will be of interest in the future to contrast the success of enzyme replacement that requires infusion with orally delivered drugs for the treatment of Gaucher's and Fabry's diseases. Oral drugs are clearly more convenient; however, the side effects and long-term toxicitv must be determined.

Long-term data from type 1 Gaucher patients at 24 months show a progressive improvement on the results previously obtained after 12 and 18 months of treatment with OGT-918. Those Gaucher patients that reached the 24-month time point have continued into their third year of therapy. Chitotrio-sidase activity, as a surrogate of activity in patients, is a biochemical marker related to the disease.

Aldurazyme is an enzyme replacement therapy for the treatment of MPS I disease. Phase III results with aldurazyme warranted filingfor marketing approval in 2002. MPS I is a genetic disease caused by the deficiency of a-L-iduronidase, an enzyme normally required for the breakdown of GAGs. The normal breakdown of GAGs is incomplete or blocked if the enzyme is not present in sufficient quantity. The accumulation of GAGs in the lyso-somes of the cell cause MPS I.

Patients with MPS I are usually diagnosed in childhood and get progressively worse, leading to severe disability and early death. During the course of the disease, the build-up of GAGs results in inhibited growth and mental development, impaired vision and hearing, reduced cardiovascular and pulmonary function, and joint deformities. About 3000-4000 patients in developed countries have MPS I.

Arylsulfatase B (N-acetylgalactosamine 4-sulfatase) is a deficient enzyme in patients with the genetic defect disease MPS VI. Like MPS I, GAGs are only partially broken down, and carbohydrate residues build relentlessly in the lysosomes of cells. Also like a-L-iduroni-dase replacement, the exogenous supply of ar-ylsulfatase could breakdown the stored GAGs and cellular function could be restored.

Aryplase is a specific form of the recombinant human enzyme, arylsulfatase B. In a phase I trial, the enzyme was well tolerated, and there were no drug-related serious adverse events and no significant allergic reactions to the infusions. Urinary GAG excretion was reduced by a mean of 70% in the high dose group and 55% in the low dose group. Urinary GAG excretion is a biomarker for MPS.

Long-term observation of the development process in the pharmaceutical industry indicates that roughly one of every six therapeutics (17%) submitted as investigational new drug applications go on to be filed successfully as New Drug Applications with the U.S. Food and Drug Administration. In Table 7.2 , 15 of 26 carbohydrate-based therapeutics (58%)are still in development. Clearly, more carbohydrate-based therapeutics in development will be discontinued; however, if the industrial average holds, at least four of the therapeutics in development will go on to be successful drugs.

2.3 Agents in Research

Research agents are the source of new drugs. Research on carbohydrate-based agents that may have use as drugs is increasing; however, getting specific structural information is more difficult. Large pharmaceutical companies that are a traditional source of new drugs, including the early publication of structures, have not wholly endorsed carbohydrate chemistry or glycobiology. In contrast, small biotechnical companies that have focused on these technologies .aggressively advertise "products in the R&D pipeline" without disclosing specific molecular information that describe the potential products.

Areas of special interest in carbohydrate drug research include the treatment of Helicobacter pylori gastritis and prion-induced CNS disease. The following is organized in the approximate order as Sections 2.1 and 2.2, starting with diabetes research that continues to attract new carbohydrate-based agents.

2.3.1 Diabetes. DYN12 is a small molecule that reduces plasma concentrations of 3-de-oxyglucosone (3DG) in diabetic rats by 50%. 3DG is a highly reactive molecule that can cross-link proteins, causing them to change or lose function, including the inactivation of certain enzymes. 3DG is also a proven factor in the development of advanced glycation end products (AGEs), which are implicated in the development of diabetic kidney disease, arteriosclerosis, and other diseases. Amadorase or the closely related fructoseamine-3-kinase is the putative enzyme responsible for the formation of most of the 3DG in the body (59).

2.3.2 Gastrointestinal System. The human specific gastric pathogen, H. pylori, has emerged as the causative agent in chronic active gastritis and peptic ulcer disease (60). The bacterium is unique in its carbohydrate-binding complexity. The complete genome sequence of H. pylori reveals a surprisingly large part coding for outer surface proteins, reflecting a complex interrelation with the environment. Specific binding molecules are many and include polyglycosylceramide (61), and sialic acid conjugates (62). Recently, a sialy-lated receptor analog was evaluated in clinical trials with H. pylori-infected patients with promising results (63).

2.3.3 CNS. Prions are composed exclusively of a single sialoglycoprotein called PrP. They contain no nucleic acid, have a mass of 30

Table 7.2 Therapeutics in Development

Name Generic (Code)

Mitemcinal (11) (GM-611)

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