DRUG CANDIDATES MARCH ONWARD

SCIENCE & TECHNOLOGY

A C S M E E T I N G N E W S

DRUG CANDIDATES MARCH ONWARD Therapeutics for psoriasis, cancer, Alzheimer's, and cardiovascular and muscle diseases progress STU BORMAN, C&EN WASHINGTON

IT'S OFTEN SAID LATELY THAT THE

pharmaceutical industry has been go­ing through a dry spell in developing new drugs. But if the plethora of talks on new medications at the ACS na­

tional meeting last month in Washington, D.C., is any indication, the industry's bar­ren period might not last all that long.

Researchers at the meeting discussed a wide range of new therapeutic agents un­der development. Among those described in sessions organized by the Divisions of Carbohydrate Chemistry (GARB) and of

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Medicinal Chemistry (MED I) alone were several already in clinical trials or getting close. These include drugs for psoriasis and other autoimmune conditions, cancer and tumor metastasis, melanoma, cardiovas­cular disease, and muscular dystrophy

One autoimmune and two cancer drugs were described at a CARB symposium on iminosugars, compounds in which a ring oxygen or carbon in a conventional sugar

is replaced with a nitrogen to introduce a cationic center. Iminosugars have proven to be a rich source of thera­peutic drug candidates in the past few years and have thus become a special focus of re­search attention.

Biochemistry professor Vern L. Schramm at Albert Einstein College of Medi­cine, Bronx, N.Y., and co­workers have been concen­trating on iminosugars in their efforts to identify drug leads by analyzing reaction transition states.

In the technique, an en­zyme associated with a hu­man disease is selected, the potential sur­face of the substrate transition state (the surface with which the enzyme interacts) is determined, and substrate transition-state analogs are synthesized and tested for inhibitory activity

IN EARLIER WORK, Schramm and co­workers used this approach to identify in­hibitors of human purine nucleoside phosphorylase (PNP), an enzyme associat­ed with cancer and autoim­mune diseases. P N P has been a popular target for drug design, but it has been difficult to identify highly potent inhibitors for it.

Schramm and coworkers solved this problem with transition-state analysis. They determined the transition-state structure of bovine PNP's enzyme's substrate in 1993; collab­

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orated with Industrial Research, of Low­er Hutt, New Zealand, to synthesize po­tential inhibitors; and in 1998 identified a highly potent one, the iminoribitol im­mucillin-H (Fodosine), an iminosugar of 9-deazainosine. In 2000, the compound was licensed to BioCryst Pharmaceuticals, of Birmingham, Ala., and it recently ad­vanced to clinical trials for resistant and relapsedTcell cancers and B-cell leukemia.

At the ACS meeting, Schramm and coworkers described transition-state analysis of human PNP to design a sec­ond-generation compound. It's a meth-ylene-bridged hydroxypyrrolidine called DADMe-immucillin-H, a deazaazadeoxy

methylene (DADMe) de­rivative of immucillin-H. Trade-named BCX-4208, DADMe-immucillin-H has better specificity for human P N P than immucillin-H, and BioCryst Pharmaceuti­cals currently has it in Phase I trials for psoriasis and oth­er autoimmune disorders.

Schramm and coworkers also recently used transition-state analysis to identify a family of tightly binding hy­droxypyrrolidine analogs of methylthioadenosine that

inhibit methylthioadenosine nucleosidase (MTAN). MTAN is a bacterial enzyme in­volved in quorum sensing, a phenomenon associated with biofilm formation and bac­terial pathogenicity Schramm says the new agents are among the most powerful non-covalent enzyme inhibitors ever reported, and his team hopes to develop them as bac­terial antibiotics.

Also on the trail of imi-nosugar-based drugs are Yoshio Nishimura, associate director of the Microbial Chemistry Research Center, Tokyo, and coworkers. They are pursuing iminosugar in­hibitors of enzymes involved in tumor metastasis as po­tential cancer therapeutics.

According to Nishimura, tumor metastasis occurs by a complex mul­tistage process that includes tumor inva­sion through blood vessel membranes. To

Iminosugars have proven to be a rich source of therapeutic drug candidates in the past few years and have thus become a special focus of research attention. W W W . C E N - 0 N L I N E . O R G C&EN / SEPTEMBER 26, 2005 39

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enter and exit blood vessels, many kinds of tumor cells secrete heparanase to break down vascular membranes. Nishimura and coworkers have synthesized geminal-di-amine 1-N-iminosugars that block the ac­tivity of heparanase and thereby inhibit tumor metastasis efficiently in animal models.

Among these are SF-4 and SDD-8, po­tent inhibitors of heparanases associated with melanoma. Both have been shown to prevent cancer cell invasion in membrane assays and to potently suppress pulmonary metastasis of tumors in mice, and neither has shown toxicity in the mouse studies. In addition, "we have developed a better can­didate and are now evaluating its activity in vivo," Nishimura said.

The agents are candidates for chemo-therapeutics to prevent cancer spread. The researchers are still trying to opti­mize them, and "a company is interest­ed in them for preclinical trials," Nishi­mura said.

Meanwhile, professor of pediatrics and biochemistry and molecular biology Stephan Ladisch of Children's National Medical Center and George Washington University School of Medicine, Washing­ton, D.C., and coworkers are trying to curb tumor growth with iminosugar inhibitors of tumor ganglioside synthesis.

The synthesis and secretion of ganglio-sides by tumor cells has been shown to block immune responses against tumor growth and also to promote angiogenesis, the development of blood vessels to sup­ply tumors. Therefore, inhibiting ganglio­side synthesis might be an effective way to fight cancer.

Ladisch and coworkers identified an orally available iminosugar, OGT2378, that inhibits glucosylceramide synthesis, a process upon which ganglioside synthe-

This novel approach to treating cancers could serve as an alternative to traditional therapies with harsh side effects.

yet know the precise molecular mecha­nism of the effect, "what we do know is that we are changing the tumor's own me­chanics to stop its growth," he said. "This novel approach to treating cancers could serve either as an alternative to tradition­al cancer-fighting therapies with harsh side effects—such as chemotherapy and radi­ation treatment—or as a supplement to

sis depends. The iminosugar has been shown to curtail melanoma growth in treat­ed mice to one-tenth that in control mice.

"Cancer cells produce gangliosides at a much more rapid rate than do normal cells," Ladisch explained. "By interfering with this process, we can stop a tumor from growing in a rather dramatic fash­ion without damaging the normal tissue surrounding it."

Although Ladisch and coworkers do not

INS50589

these standard treatments." It may still be several years, however, before human clin­ical trials are carried out, Ladisch said.

At a MEDI session on neurodegenera­tive diseases, Mark A. Findeis, vice presi­dent of research at Satori Pharmaceuticals, Boston, told attendees about his team's search for therapeutic approaches to Alzheimer's disease.

Alzheimer's is the most common neu­rodegenerative disease, currently afflict­ing about 4.5 million people in the U.S., Findeis said. Current therapies are con­sidered palliative in that they typically can slow progression of the disease by months but cannot halt the inevitable

decline of Alzheimer's patients. Findeis and coworkers believe they have identified a com­pound that may repre­sent a new kind of Alz­heimer's treatment.

The disease's early presymptomatic stage is characterized by the development in the brain of deposits formed from Ap42, a long form of amy-loid-P peptide (Ap). "Many of the mu­tations known to be associated with in­herited forms of Alzheimer's disease specifically increase the level of this form of Ap," Findeis said. Ap42 is also known to be more prone to misfold and aggregate than shorter forms of Ap and to be more toxic to cells in its aggregated form. Re-

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searchers are thus trying to find ways to lower levels of "long Ap."

Findeis and coworkers licensed a botan-ical extract from the Mayo Clinic, Rochester, Minn., and isolated specific compounds associated with A(3-lowering activity One of these, SP1, is the group's lead compound for development.

SP1 potently and selectively lowers lev­els of A(342 in cellular assays and has prom­ising activity in animals. It is structurally distinct from and orders of magnitude more potent than previously known A(3-lowering agents. 'Alas, we are not quite yet ready to show the world what this structure is," Findeis said.

In another MEDI session, James G. Douglass I I I , a principal investigator in medicinal chemistry at Inspire Phar­maceuticals, Durham, N.C., discussed INS50589, a potent and selective inhibitor of platelet aggregation that is being devel­oped for use in acute treatment of cardio­vascular diseases. The drug is "reversible," meaning that its activity dissipates quick­ly when administration is discontinued, permitting levels of platelet aggregation

SNT197958

to return to normal. Platelet aggregation forms thrombi (blood-factor aggregates), which can cause strokes, heart attacks, and other problems.

In the body, adenosine 5'-diphosphate (ADP) is one of the main regulators of platelet aggregation and consequent thrombus formation. This process begins when two G-protein-coupled receptors, P2Yj and P2Y12, are activated simulta­neously by ADP. The receptors are at­tractive targets for antithrombotic med­ications, because inhibiting the binding of ADP at either one reduces platelet ag­gregation. "We studied the structure-ac­tivity relationships of modified mono- and dinucleotides at P2Y12 and identified lipophilic modifications to the ribose and base moieties that imparted potent, se­lective, and reversible antagonist prop­erties at this receptor," Douglass said. These studies led to the identification of INS50589 as a drug candidate, owing to

its strong binding to and potent inhibi­tion of the P2Y12 receptor.

In preclinical studies and in a recently completed Phase I trial, the compound was shown to be a potent and reversible inhibitor of platelet aggregation. Inspire plans to develop it as an agent that will in­hibit platelet aggregation and activation during cardiopulmonary bypass proce­dures. The drug's reversibility would en­able normal platelet function to be restored quickly after surgery, potentially reducing postoperative complications such as blood loss and minimizing the need for transfu­sions of blood or blood products.

ANOTHER AGENT discussed in a MEDI session is an inhibitor of the enzyme cal-pain that's being developed as a treat­ment for Duchenne muscular dystrophy (DMD).

D M D is a recessive X chromosome-linked disorder characterized by progres­sive muscle wasting. It is generally diag­nosed at about the time babies start to walk, and it affects approximately one in 3,500 newborn boys worldwide.

Affected patients inevitably become wheelchair-bound as teenagers and die at a young age from heart or respiratory failure, said senior scientist Holger Herzner of Santhera Pharma­ceuticals, Liestal, Switzerland. So far, no effective treatment is available to slow or stop such muscle deterioration.

The condition is caused by mu­tations of the dystrophin gene, which lead to a deficit of func­

tional dystrophin, a structural protein in cells. Dystrophin deficiency, in turn, caus­es the calcium-dependent enzyme calpain to become activated, resulting in muscle damage from abnormal cleavage of muscle cell proteins. According to Herzner, "There is strong evidence from animal experi­ments that inhibition of this enzyme can substantially slow down the progression of muscle deterioration."

Herzner and coworkers at Santhera have developed a series of small-molecule cal­pain inhibitors optimized for cellular up­take into muscle cells. Peptide-derived a-ketoamides such as SNT197958 exhibited nanomolar activity in the group's in vitro assays and have also shown promising ac­tivity in mdx mice, an animal model for DMD. "Currently, Santhera is performing preclinical toxicology and pharmacokinetic tests as a further step to develop these in­hibitors as a treatment option for DMD," Herzner said. •

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