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  • 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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    In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

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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); -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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    In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

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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 compoundis 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 relativel

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