[ACS Symposium Series] Medicinal Inorganic Chemistry Volume 903 || Medicinal Inorganic Chemistry: Promises and Challenges

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<ul><li><p>Chapter 2 </p><p>Medicinal Inorganic Chemistry: Promises and Challenges </p><p>John W. Kozarich </p><p>ActivX Biosciences, Inc., 11025 North Torrey Pines Road, La Jolla, CA 92037 </p><p>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. </p><p>Introduction: Quest for Chemical Diversity </p><p>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 </p><p>4 2005 American Chemical Society </p><p>Dow</p><p>nloa</p><p>ded </p><p>by Y</p><p>OR</p><p>K U</p><p>NIV</p><p> on </p><p>Oct</p><p>ober</p><p> 19,</p><p> 201</p><p>4 | h</p><p>ttp://</p><p>pubs</p><p>.acs</p><p>.org</p><p> P</p><p>ublic</p><p>atio</p><p>n D</p><p>ate:</p><p> Aug</p><p>ust 2</p><p>5, 2</p><p>005 </p><p>| doi</p><p>: 10.</p><p>1021</p><p>/bk-</p><p>2005</p><p>-090</p><p>3.ch</p><p>002</p><p>In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. </p></li><li><p>5 </p><p>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. </p><p>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. </p><p>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. </p><p>Promise of Medicinal Inorganic Chemistry </p><p>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, </p><p>Dow</p><p>nloa</p><p>ded </p><p>by Y</p><p>OR</p><p>K U</p><p>NIV</p><p> on </p><p>Oct</p><p>ober</p><p> 19,</p><p> 201</p><p>4 | h</p><p>ttp://</p><p>pubs</p><p>.acs</p><p>.org</p><p> P</p><p>ublic</p><p>atio</p><p>n D</p><p>ate:</p><p> Aug</p><p>ust 2</p><p>5, 2</p><p>005 </p><p>| doi</p><p>: 10.</p><p>1021</p><p>/bk-</p><p>2005</p><p>-090</p><p>3.ch</p><p>002</p><p>In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. </p></li><li><p>6 </p><p>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). </p><p>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). </p><p>Figure 1. Arsphenamine (trade name Salvarsan), the result of the first modern medicinal chemistry program, discovered by Paul Erlich in 1909for the </p><p>treatment of syphilis. </p><p>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. </p><p>Drug Discovery and Development Today </p><p>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, </p><p>Dow</p><p>nloa</p><p>ded </p><p>by Y</p><p>OR</p><p>K U</p><p>NIV</p><p> on </p><p>Oct</p><p>ober</p><p> 19,</p><p> 201</p><p>4 | h</p><p>ttp://</p><p>pubs</p><p>.acs</p><p>.org</p><p> P</p><p>ublic</p><p>atio</p><p>n D</p><p>ate:</p><p> Aug</p><p>ust 2</p><p>5, 2</p><p>005 </p><p>| doi</p><p>: 10.</p><p>1021</p><p>/bk-</p><p>2005</p><p>-090</p><p>3.ch</p><p>002</p><p>In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. </p></li><li><p>7 </p><p>while somewhat formulaic once a development candidate is chosen, presents an often bewildering array of regulations. </p><p>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. </p><p>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). </p><p>Medicinal Inorganic Chemistry Therapeutics Scorecard </p><p>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). </p><p>Dow</p><p>nloa</p><p>ded </p><p>by Y</p><p>OR</p><p>K U</p><p>NIV</p><p> on </p><p>Oct</p><p>ober</p><p> 19,</p><p> 201</p><p>4 | h</p><p>ttp://</p><p>pubs</p><p>.acs</p><p>.org</p><p> P</p><p>ublic</p><p>atio</p><p>n D</p><p>ate:</p><p> Aug</p><p>ust 2</p><p>5, 2</p><p>005 </p><p>| doi</p><p>: 10.</p><p>1021</p><p>/bk-</p><p>2005</p><p>-090</p><p>3.ch</p><p>002</p><p>In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. </p></li><li><p>8 </p><p>Figure 2. The Investigational New Drug review process chart describing the reviews and decision points leading to an acceptable IND application. </p><p>Dow</p><p>nloa</p><p>ded </p><p>by Y</p><p>OR</p><p>K U</p><p>NIV</p><p> on </p><p>Oct</p><p>ober</p><p> 19,</p><p> 201</p><p>4 | h</p><p>ttp://</p><p>pubs</p><p>.acs</p><p>.org</p><p> P</p><p>ublic</p><p>atio</p><p>n D</p><p>ate:</p><p> Aug</p><p>ust 2</p><p>5, 2</p><p>005 </p><p>| doi</p><p>: 10.</p><p>1021</p><p>/bk-</p><p>2005</p><p>-090</p><p>3.ch</p><p>002</p><p>In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. </p></li><li><p>9 </p><p>Figure 3. The New Drug Application review process chart describing the reviews and decision points leading to FDA approval </p><p>Dow</p><p>nloa</p><p>ded </p><p>by Y</p><p>OR</p><p>K U</p><p>NIV</p><p> on </p><p>Oct</p><p>ober</p><p> 19,</p><p> 201</p><p>4 | h</p><p>ttp://</p><p>pubs</p><p>.acs</p><p>.org</p><p> P</p><p>ublic</p><p>atio</p><p>n D</p><p>ate:</p><p> Aug</p><p>ust 2</p><p>5, 2</p><p>005 </p><p>| doi</p><p>: 10.</p><p>1021</p><p>/bk-</p><p>2005</p><p>-090</p><p>3.ch</p><p>002</p><p>In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. </p></li><li><p>10 </p><p>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). </p><p>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 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 </p><p>Dow</p><p>nloa</p><p>ded </p><p>by Y</p><p>OR</p><p>K U</p><p>NIV</p><p> on </p><p>Oct</p><p>ober</p><p> 19,</p><p> 201</p><p>4 | h</p><p>ttp://</p><p>pubs</p><p>.acs</p><p>.org</p><p> P</p><p>ublic</p><p>atio</p><p>n D</p><p>ate:</p><p> Aug</p><p>ust 2</p><p>5, 2</p><p>005 </p><p>| doi</p><p>: 10.</p><p>1021</p><p>/bk-</p><p>2005</p><p>-090</p><p>3.ch</p><p>002</p><p>In Medicinal Inorganic Chemistry; Sessler, J., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005. </p></li><li><p>11 </p><p>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 a...</p></li></ul>