Chapter 2

Medicinal Inorganic Chemistry: Promises and Challenges

John W. Kozarich

ActivX Biosciences, Inc., 11025 North Torrey Pines Road, La Jolla, CA 92037

Medicinal inorganic chemistry remains a field of great promise with many challenges. The potential for a major expansion of chemical diversity into new structural and reactivity motifs of high therapeutic impact is unquestionable.

Introduction: Quest for Chemical Diversity

The search for new, effective medicines for human health and for the nearly $500 billion world-wide pharmaceutical industry invariably requires the ability to access new regions of chemical diversity. Chemical diversity for the purposes of this discussion refers to the arrangements of atoms within molecules that create a broad range of structural, spatial and reactivity combinations that can be interrogated against a biological or pharmacological response. We normally refer to these collections of chemically diverse compounds as libraries and the interrogated responses as assays. The sorting of chemical libraries against

4 © 2005 American Chemical Society

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biological assays has been the linchpin of drug discovery for over one hundred years. The range of biological assays available today is unprecedented - from whole animal evaluation that was the mainstay of early discovery a few decades ago to miniaturized, high-throughput, multi-array analysis against individual molecular targets. The range of chemical diversity that can be accessed is stupendous.

The drug discovery industry has created the lion's share of this chemical diversity. During the past century, organic medicinal chemists have synthesized millions of new compounds - some purely synthetic creations; some variations on the natural products that have been identified along the way; some as single well-characterized compounds; some as mixtures of isomers or related compounds. In general, the diversity libraries created by medicinal chemists have largely been a historical record of the therapeutic targets their particular company has pursued. Thus, some libraries are rich in steroid-type structures and others are rich in antibiotic pharmacophores. The advent of combinatorial chemistry and chemoinformatics over the past 15 years has enabled drug discovery companies to quantify the scope of chemical diversity within their libraries, identify sparsely-represented regions, and rapidly fill those regions in with many millions of synthetic molecules as either single entities or as a cocktail of related compounds.

Despite the explosion in medicinally-oriented chemical diversity, inorganic compounds have not captured a significant share of library space within the pharmaceutical sector. Despite the impressive promise of medicinal bioinorganic chemistry clearly revealed in the subsequent chapters of this book, few inorganic compounds have reached the goal of FDA-approved drug. The reasons for this are at once simple and complex. I offer my own perspective on the promise and challenges of medicinal bioinorganic chemistry from the vantage point of a scientist who has functioned at the periphery of this discipline but believes that the field will play a crucial role in our understanding of human biology and in the development of innovative new medicines.

Promise of Medicinal Inorganic Chemistry

The use of metals in medicine is as old as recorded human history (/). Modern successes span from what was arguably the first medicinal chemistry screening campaign by Paul Erlich to the recent development of sophisticated bioimaging agents. The therapeutic applications of metal-based drugs span virtually every disease area: anticancer (Al, Ga, In, Ti, Ru, Pt, Au, Sn); antimicrobial (As, Cu, Zn, Ag, Hg, Bi); antiarthritic (Au); antipsychotic (Li); antihypertensive (Fe, Zn); antiviral (Li, Pt, Au, W, Cu); antiulcer (Bi); antacids (AI, Na, Mg, Ca); metalloenzyme mimetics (Mn, Cu, Fe); radiotherapy (e.g. Re,

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Y, Pb); ß-emitters (90Y, 212Bi); and metal chelators. Diagnostic applications are equally impressive and have received generally greater acceptance in mainstream medical practice: Radiosensitization (Pt, Ru); magnetic resonance imaging (e.g. Mn, Gd, Fe); X-ray imaging (e.g. Ba); radio-imaging (e.g. 99mTc, l l l l n ) . Recent reviews have nicely described the scope and potential of these applications {2,3).

Nearly one hundred years ago, modern medicinal chemistry was off to an impressive start in a decidedly inorganic direction. Paul Erlich developed the paradigm for medicinal chemistry and drug screening in his search for a new arsenic compound for the treatment of syphilis. He created a chemical library of organoarsenates designed to decrease the reactivity/toxicity of arsenic while retaining or increasing its therapeutic efficacy against the disease. Erlich screened a library of compounds and discovered that compound number 606 had the characteristics he wanted. The compound was arsphenamine (trade name, Salvarsan; Figure 1).

Figure 1. Arsphenamine (trade name Salvarsan), the result of the first modern medicinal chemistry program, discovered by Paul Erlich in 1909for the

treatment of syphilis.

This compound became the standard of treatment for syphilis for over thirty years until it was phased out by other arsenicals and, finally, penicillin. Erlich's approach - create chemical diversity and assay for improved therapeutic properties - has changed little in the last century with the exception of the vast expansion of chemical space and the sophistication of the biological assays.

Drug Discovery and Development Today

The process of drug discovery and development today is vastly more complex and expensive than a century ago. The Tufts Center for the Study of Drug Development estimated in 2001 that the average approval cost per new prescription drug is $802 million which was based on information from 10 companies; included were expenses of project failures and the impact that long development times have on investment costs (4). The development process,

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while somewhat formulaic once a development candidate is chosen, presents an often bewildering array of regulations.

The requirements for the filing of an IND (Investigational New Drug) application are focused on safety, chemical manufacturing and clinical protocols and are the same for metal therapeutics (Figure 2) (5). Animal pharmacology and toxicology studies are required to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Animal studies to support the scientific hypothesis underlying drug efficacy are also important but not the primary focus of the safety review. Manufacturing information pertaining to the composition, manufacture, stability, and controls used for manufacturing the drug substance and the drug product is assessed to ensure the company can adequately produce and supply consistent batches of the drug. Detailed protocols for proposed clinical studies are assessed to determine whether the initial-phase trials will expose subjects to unnecessary risks. Information on the qualifications of clinical investigators-professionals (generally physicians) who oversee the administration of the experimental compound—is also reviewed to determine whether they are qualified to fulfill their clinical trial duties.

Once the FDA has determined that it is safe to proceed, the clinical trials and subsequent NDA (New Drug Application) must address three issues: whether the drug is safe and effective for its proposed use(s), and whether the benefits of the drug outweigh its risks; whether the drug's proposed labeling is appropriate, and, if not, what the drug's labeling should contain; whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity (Figure 3). If these criteria are adequately addressed the FDA will approve the drug for the specific disease indications claimed (5).

Medicinal Inorganic Chemistry Therapeutics Scorecard

The number of metal-based drugs that have achieved FDA approval is remarkably few. Consider all oncology indications where the tolerance for drug side-effects and the demand for new treatments are relatively high. From 1949 to 2003, the FDA approved 89 new molecules that have been granted 210 specific claims for oncology treatments. Only 6 of these molecules are unambiguously defined as metal complexes or inorganics and these molecules have been granted a total of 9 claims for oncology. Thus, only 7% of the new molecules and 4% of specific claims approved by the FDA for oncology over the past 50+ years represent the fruits of medicinal inorganic chemistry. This is consistent with pharmaceutical sales; of the -$16 billion world-wide oncology drug market in 2001, $1 billion was accounted for by the platinum(II) drugs (6,7).

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Figure 2. The Investigational New Drug review process chart describing the reviews and decision points leading to an acceptable IND application.

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Figure 3. The New Drug Application review process chart describing the reviews and decision points leading to FDA approval

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The 6 metal complexes/inorganics that have made it across the FDA goal line are revealing. The 3 most significant are the covalent DNA-crosslinking platinum(II) complexes which are described in later chapters. Cisplatin (Platinol; Bristol Myers Squibb) received FDA-approval in 1978 for the treatment of ovarian and testicular cancers. Approval came 17 months after NDA filing. In 1993, an additional claim for transitional cell bladder cancer was approved 4 months after filing. Cisplatin has become a front-line cancer agent and has an impressive 90% cure rate for testicular cancer. Nephrotoxicity is the major adverse effect. In 1989, Bristol Myers Squibb received approval of carboplatin (Paraplatin) for the treatment of recurrent ovarian cancer a rapid 8 months after filing. A second claim for carboplatin was approved in 1991 for advanced ovarian cancer. The limiting toxicity for carboplatin is myelosuppression. Another platinum(II) variation on cisplatin, oxaliplatin (Eloxatin; Sanofi-Synthelabo) was approved for the treatment of colon or rectal cancer in combination with 5-fluorouracil/leukovorum (5-FU/LV). Accelerated approval in 2002 was granted 6 weeks from filing, a clear indication on the lack of treatment for this devastating cancer. Neuropathy appears to be the limiting toxicity for oxaliplatin. These 3 platinum(II) drugs and several others in the clinic represent a classic expansion of chemical diversity, reminiscent of Erlich's work, around a pharmaceutically useful motif to alter pharmacological properties. Unfortunately, the platinum(II) class currently remains the only example of medicinal inorganic chemistry in its fullest potential for drug discovery (6).

In 2002, the first radiopharmaceutical, ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals), received accelerated FDA approval for the treatment of low-grade, B-cell, Non-Hodgkin's Lymphoma (NHL). Zevalin is an immunoconjugate of IDEC's successful antibody drug for NHL, Rituxan, and a high affinity chelation site for the inorganic radionuclides indium-111 or yttrium-90. Rituxan itself was the first monoclonal antibody approved for cancer therapy; it binds specifically to the CD20 antigen expressed on greater than 90% of B-cell NHLs. Thus, Rituxan targets and destroys only Β cells. Zevalin is used for low-grade, B-cell NHLs that have not responded to chemotherapy or to Rituxan alone. The antibody-targeted chelation site for the radionuclide permits the delivery of high dose radiation (mCi's per dose) while reducing the amount of full body radiation. Zevalin received accelerated approval although long-term clinical efficacy remains to be established. This type of antibody-targeted delivery has considerable potential for metal-based therapeutic, as well as diagnostic, applications (6). The two remaining FDA-approved oncology "drugs" are true inorganics. In 1997, an aerosol formulation of talc (Sclerosol; Bryan Pharmaceuticals) was approved for the treatment of malignant pleural effusion associated with lung cancers. The talc, which has a general structure of Mg3Si4Oio(OH)2, is delivered directly into the pleural cavity and functions as a sealant to prevent re-accumulation of fluids into to lungs through cancer-associated lesions. Calling this an oncology drug is not entirely accurate; it is better viewed as supportive

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therapy. The final and, in many ways, the most astounding approval was for Trisenox (Cell Therapeutics) in 2000. Trisenox is an i.v. formulation of arsenic trioxide (As 40 6), a fact that must have Paul Erlich scratching his head in bewilderment. But even more remarkable, was the speed of the FDA in approving one of the most toxic arsenic-containing compounds. Trisenox was approved 6 months after NDA filing for an orphan status indication as a second line treatment of relapsed or refractory acute promyelocytic leukemia (APL) following trans-retinoic acid (ATRA) plus an anthracycline. In one multicenter study, the remission rate was found to be 70%. Finally, it is sobering to note that Trisenox, a toxic, medicinal chemistry-unadorned arsenate, currently holds the FDA record for fastest time for any drug from initial IND filing to approval - 3 years (6)! The considerable human experience with this drug from uncontrolled studies conducted in China was a significant factor in the speed of the FDA approval. The point of the above analysis is that there is both good news and bad news for medicinal bioinorganic chemistry. The good news is that the field has at least one clear-cut therapeutic success story, the platinum(II) complexes that has all the elements of a bona fide medicinal chemistry program with continued potential for new drugs. Another positive is that the FDA will move aggressively to approve new drugs, even less than optimal ones, if they address major unmet medical needs. Recent changes in the FDA appear to be moving them toward an even more proactive position. This is good news for the pharmaceutical industry in general. There is also bad news for medicinal inorganic chemistry to consider. Most obvious is the thin record of therapeutic successes over the past half-century in a complex, multi-etiological disease (cancer) with a high tolerance for side-effects in drugs and many niches for accelerated approval for unmet medical needs. Why is the record so thin? Why has progress been so slow and, in some cases (such as Trisenox) essentially retrograde to modern medicinal chemistry? The reasons lie in the fundamentals of how pharmaceutical drug discovery is conducted and who conducts it.

Diagnostics versus Therapeutics

The development of metal diagnostics has faired better than metal therapeutics. For diagnostics in general, a key requirement is that the compound must have minimal or no biological effect on the organism. Significant perturbation of the organism by a diagnostic undermines the validity of the information obtained. This requirement necessarily puts dosing of the compound below the no effect level for any therapeutic or potentially toxic effects. Diagnostics thus require high sensitivity. Here, metals are robust, due to their nuclear and/or electronic properties, so low doses and high sensitivity

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substantially reduce toxicity problems. Metal therapeutics, of course, must have a biological effect on a disease process, thereby requiring higher doses. With the possible exception of radiopharmaceuticals, the chemical properties of the metal come into play increasing the likelihood of toxic effects. Managing the chemical reactivity of metal therapeutics is a major challenge and in most cases the basis for efficacy.

Medicinal chemistry: organic versus inorganic

The vast majority of medicinal chemists in the pharmaceutical industry are trained as organic chemists. The philosophy that pervades medicinal chemistry programs is organocentric. Although the application of inorganic chemistry to drug discovery as we noted earlier began a century ago, the emergence of bioinorganic chemistry as a pharmaceutical discipline, as exemplified in this book, was much slower to develop. Thus, organic chemistry which is the primary language of natural products chemistry, the reference point for most drugs, gained a decisive upper hand during the emergence of the major pharmaceutical research labs like Merck and Pfizer in the '30s and 40s from their beginnings as fine chemical suppliers. For medicinal inorganic chemistry to succeed, the chemical culture of the industry must change. This will take time and a new generation of medicinal chemists trained and willing to integrate inorganic principles into drug design.

The chemical principles that are driving drug discovery in the industry also put inorganic approaches at a disadvantage. The medicinal chemist has grown to abhor drug leads with intrinsic chemical reactivities. Although the field grew out the development of reactive drugs such as the penicillins, chemical reactivity is intimately and, sometimes, inextricably associated with adverse drug effects. For example, the penicillins and cephalosporins rely on the intrinsic reactivity of the β -lactam moiety in the molecules to specifically and covalently acylate the active site serine residue in bacterial cell wall transpeptidases. This covalent enzyme inhibition is the basis on the drugs' antibacterial activity. This reaction is highly specific for the bacterial tranpeptidases but not absolutely so. The β-lactam will occasionally acylate other amino acids, such as lysine, in other proteins, some from the mammalian host. The resulting modified proteins can lead to adverse drug effects such as the known immunogenic effects of the β-lactam family. And so it goes with many drug leads; intrinsic reactivity while useful can be difficult to control in order to maximize the therapeutic window of a compound. The focus on increasingly safer drugs has driven the medicinal chemist toward the goal of identifying unreactive compounds that rely on potent, noncovalent interaction (tight binding) with their molecular target to modulate a biological process. Unreactive drugs without covalent modification and redox

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potential generally present fewer issues with respect to toxicities or so it is believed. The development of large combinatorial libraries to explore chemical diversity is also more easily industrialized when the structure to not require sophisticated and expensive methods to deal with intrinsically reactive compounds, such as, redox-active metal-containing compounds. In contrast to purely organic drug leads, most metal complexes that medicinal inorganic chemists are pursuing have intrinsic reactivities that are essential to their biological effect. The rich redox chemistries of the SOD mimics and vanadium complexes are critical to the biological efficacy but also present challenges with respect to the management of side effects. Thus, the medicinal inorganic chemist is engaged in a quest to design metal complexes that harness the metal reactivities to optimize a specific beneficial effect while the medicinal organic chemist is committed to the design of molecules that function as pure tight binders devoid of as much reactivity as possible. The pharmaceutical industry clearly favors the latter path and, until more successes can be marked on the medicinal inorganic score card, it will be difficult to change that trajectory. In the biotechnology arena, companies like Berlex which developed the first MRI agent in 1988 and Pharmcyclics which is developing metal-containing texaphyrins are two notable standard-bearers for the medicinal inorganic chemistry approach to diagnostics and therapeutics.

Conclusions

Medicinal inorganic chemistry remains a field of great promise with many challenges. The potential for a major expansion of chemical diversity into new structural and reactivity motifs of high therapeutic impact is unquestionable. As evidenced from the contributions to this book, the field is thriving largely in academic institutions, small biotech companies and some pharmaceutical companies with diagnostic units. A significant presence in the therapeutic arena of Big Pharma has yet to emerge. Creating some key therapeutic breakthroughs that capture the interest of the pharmaceutical industry is essential to ensure the growth of the field in the future.

References

(1) Orvig, C.; Abrams, M.J. Chem. Rev. 1999, 99, 2201-2203. (2) Orvig, C.: Thompson, K.H. Science 2003, 300, 936-939. (3) Zhang, C.X.; Lippard, S.J. Curr. Op. Chem. Biol 2003, 7, 481-489 and

references cited therein.

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(4) The study can be accessed at http://csdd.tufts.edu/InfoServices/Publications.asp .

(5) The IND and NDA review processes can be accessed at http://www.fda.gov .

(6) Information on approved oncology drugs may be obtained from http://www.fda.gov/cder/regulatory/applications/ind_page_l.htm .

(7) In this analysis I am excluding drugs, such as bleomycin, which, while strong evidence exists for the role of metal ions in the mechanism of action, was not formulated nor developed as a specific metal complex.

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