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Medicinal chemists: What are they? Who is good at it? What is the future?

Medicinal chemists: What are they? Who is good at it? What is the future?. Christopher A. Lipinski Scientific Advisor Melior Discovery clipinski@meliordiscovery.com. What is a medicinal chemist?.

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Medicinal chemists: What are they? Who is good at it? What is the future?

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  1. Medicinal chemists: What are they? Who is good at it? What is the future? Christopher A. Lipinski Scientific Advisor Melior Discovery clipinski@meliordiscovery.com Rhode Island College. October 6, 2007

  2. What is a medicinal chemist? • Medicinal chemistry is synthetic chemistry plus 10-15 years of biomedical chemistry pattern recognition • Medicinal chemists live in industry • Biologists live in academia • Academic biology – medicinal chemistry disconnect Rhode Island College. October 6, 2007

  3. Incomprehensible “Reality” depiction in chemistry is incomprehensible to biology / genomics and vice versa. Chemistry much closer to pathology than to biology / genomics. Graphical pattern recognition is the forte of chemists Rhode Island College. October 6, 2007

  4. Medicinal chemists - hiring • Pharma big • hire the best synthetic chemist • train the medicinal part on the job • Pharma little • hire a chemist with multidisciplinary skills • Train the synthesis part on the job • Patterns of best converge after 15 years Rhode Island College. October 6, 2007

  5. Medicinal chemists - managing • Innovation, 95% is predictable • managing is a must • Innovation, 5% unpredictable • managing can destroy • need time to think • Wise neglect • Dedicated think tank Rhode Island College. October 6, 2007

  6. Medicinal chemists - personality • Pragmatic • like to make things • Pattern recognition skills • love chemistry structures • Social • share chemistry information • Work well in a group setting Rhode Island College. October 6, 2007

  7. Chemistry in drug discovery • Hit to lead chemistry • Efficient chemistry to determine whether the series has the potential to progress • parallel synthesis, 30-50 compound libraries • microwave chemistry • solid phase scavengers • Lead optimization • Traditional medicinal chemistry optimization • tweaking of the structure • one at a time chemistry Rhode Island College. October 6, 2007

  8. AstraZeneca "Generic Lead Target Profile" for taking HTS hits to Leads (1) Potency 100nM Rat hepatocyte intrinsic clearance < 14uL/min/10x6 cells Human microsome intrinsic clearance < 23ul/min/mg Rat IV clearance < 35ml/min/kg Volume > 0.5L/kg t1/2 > 0.5 hr Rat PO bioavailability > 10% Plasma Protein binding < 99.5% Solubility > 10ug/ml Rhode Island College. October 6, 2007

  9. AstraZeneca "Generic Lead Target Profile" for taking HTS hits to Leads (2) ClogP < 3 LogD < 3 Mol Wt < 450 P450 inhibition IC50 > 10uM for 5 major isozymes HERG screening Early toxicity in vitro screens Clear SAR around potential lead Selectivity - Use PanLabs/Cerep batteries Structure must provide patent opportunities Need in vivo biological validation Rhode Island College. October 6, 2007

  10. Combinatorial chemistry - historical • 1992-1997 “storage of the combinatorial libraries in garbage dumpsters would have much improved drug discovery productivity” • poor identity • poor purities • mixtures of compounds • poor design • fascination with huge numbers Rhode Island College. October 6, 2007

  11. Combinatorial chemistry today • Reliable and useful • Solution phase more common than solid phase synthesis • Small automated libraries, 30-50 compounds • Identity is correct • Purity > 90 – 95% • Concentration an issue for 15% of samples • HTS screening source as DMSO stocks • Screening libraries are ruthlessly culled Rhode Island College. October 6, 2007

  12. The “rule of five” mnemonic • Poor absorption or permeation are more likely when there are: • More than 5 H-bond donors. • The MWT is over 500. • The CLog P is over 5 (or MLOGP is over 4.15). • The sum of N’s and O’s is over 10. • Substrates for transporters and natural products are exceptions Rhode Island College. October 6, 2007

  13. Parameters for 7483 INN/USAN Drugs Define the 90% Limits for Oral Drug Absorption. Rhode Island College. October 6, 2007

  14. Target validation versus drug discovery • Use a chemical tool to probe biology • relaxed chemistry criteria permissible • chemical costs go down • 50,000 or fewer compounds in HTS • Drug discovery • strict chemistry criteria • cost as high as $200-400 for 15 mg compound • 500,000 compounds in an HTS Rhode Island College. October 6, 2007

  15. Genomics, help or hindrance 1% success, NPV $34M, Decision Resources March 29, 2004 Rhode Island College. October 6, 2007

  16. More on genomics ’65% of the audience at PharmaDiscovery considered that sequencing of the human genome did not have even moderate effects on effective drug research’ Steve Carney, DDT Volume 10, Number 15 August 2005 pp 1025-1029 How many genomics targets can a portfolio afford? ‘To achieve an overall risk balance, portfolios have to be supplemented with precedented targets, me-too approaches and line extensions of existing drugs.’ Ulrich A. K. Betz, DDT Volume 10, Number 15 August 2005 pp 1057-1063 Rhode Island College. October 6, 2007

  17. Chemistry false positives • Promiscuous aggregators • Covalent modifiers • Detergents • Optical interferers • Redox agents (“alarm NMR”) • Cytotoxic agents • Chelators Rhode Island College. October 6, 2007

  18. False positives in HTS assays Remove these types of compounds from any assays These look good to biologists Rhode Island College. October 6, 2007

  19. Medicinal chemistry and biology • Medicinal chemists recognize garbage chemistry • Biologists don’t recognize bad chemistry • Biology is ruined by poor chemistry • Medicinal chemistry has an essential role Rhode Island College. October 6, 2007

  20. Chemistry “quality” and biology effort > 80% flawed compounds? Rhode Island College. October 6, 2007

  21. Historically few “innovator” targets / year 24 New Ligands in 8 Years Across Everybody Rhode Island College. October 6, 2007

  22. Non combichem innovator drugs Rhode Island College. October 6, 2007

  23. Divergent business goals • Academia - basic research • peer reviewed publications • train students / postdocs • financial viability not necessary • Pharma / Biotech - a medicine • chemical compound • fill an unmet medical need • financial return to shareholders / VC’s Rhode Island College. October 6, 2007

  24. Novel targets and innovation • A huge challenge • Equal opportunity for all players • have to make money • pharma • biotech • don’t have to make money • government • academia Rhode Island College. October 6, 2007

  25. Novel target problem solution • Technology fix • standard talk matter in conferences • Over-hype, crash, equilibrium reality • People fix • academics uncoupled from anything useful • Fix the decoupling • increase target validation information • translational research Rhode Island College. October 6, 2007

  26. Chemistry outsourcing is here today • The best in chemistry will have USA jobs • Offshore $ FTE rates 1/5 to 1/2 of USA • Outsourcing limitations: • intellectual property issues • timeliness • quality issues • communication issues • work force instability • medicinal chemistry takes time to learn Rhode Island College. October 6, 2007

  27. Sensitive to outsourcing • Easily outsourced • chemistry far from an IP decision point • longer timelines are OK • tolerance for quality control issues • single scientific discipline, not a team • single point communication is OK • known process • US based people contacts are unimportant Rhode Island College. October 6, 2007

  28. Resistant to outsourcing • Difficult to outsource • chemistry close to an IP decision point • short timelines, quick response needed • little or no tolerance for quality issues • team efforts, cross discipline interactions • detailed multi person information needed • undocumented or new or evolving process • knowing who to talk to is important Rhode Island College. October 6, 2007

  29. Protecting your career • Education, education, education • Learn the process not just the technology • Meet people, be helpful • Your resume should be a work in progress • Longer term benefit • oral presentations • posters • papers • What should your job be? • Watch what you do. What is fun for you? Rhode Island College. October 6, 2007

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