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drug discovery- history, evolution and stages

  2. Drug… Any chemical that produces a change in the body… Defined by characteristics: 1. Use or potential use in diagnosis or treatment of disease 2. Selective in their actions
  3. Need for Drug Discovery  Unmet Medical Needs:  New Diseases ,AIDS, Alzheimer’s, obesity  Low efficacy – dementia, cancer  Side effects – antipsychotics, antidepressants  Downstream health cost - (Alzheimer’s; spinal injury)  cost of therapy; (Interleukins)  costs to individual/country; (depression)  Sustain industrial activity; pharmaceutical industry employs thousands and makes a massive contribution to overseas earnings; patent expiry
  4. The changed context of drug discovery and development HISTORICAL ASPECTS  1537-first clinical trial of a novel therapy by Amboise pare  1747-James Lind introduced control groups in experiment, document citrus fruits in the diet prevent scurvy  1863- Placebos were first used  1923-concept of randomisation introduced  1931-concept of randomisation of patients to treatment in clinical trials  1945-ethical impact of clinical trial has become
  5.  1947-thse regulations enshrined in Nuremberg codex  1948-1st trial using properly randomised treatment and control groupss by medical research counsil  1964- introduction of declaration of Helsinki  Amended in 1975, 1983, 1989, 1996, 2000, 2002 and 2004
  6. Drug development  Drug development-The entire process of taking a newly discovered compound or drug through regulatory approval to the point of marketing.  During the development, the new drug or the compound should adhere to high standards in the conduct, analysis and interpretation of preclinical and clinical studies for its smooth passage through the regulatory approval phase and eventually to marketing.  Pathways of drug development are  Discovery  Preclinical development  Clinical development
  7. Choose a disease
  8. Pre-discovery  Understanding the disease  Know the underlying cause for the disease  Try to understand how genes are altered – how they affect proteins they encode  How proteins interact with each other in living cells  How those affected cells change the specific tissue they are in
  9. How drug works….  The cells in the body carry out complex molecular reactions  A mistake in one reaction might stop an important protein from being produced or over-produced – leads to body not producing enough cells (diabetes) or over production of cells (cancer)  Drug molecule affect these pathways by interacting with certain molecules along the pathway – making them more or less active or changing their activity
  10. Drug discovery  Drug discovery begins in the laboratory with scientists of various functional areas working together to identify cellular and genetic factors that play a role in specific disease  Identification of target and resource  4 steps
  11. Target Selection Biochemical Classes of Drug Targets  G-protein coupled receptors - 45%  enzymes - 28%  hormones and factors - 11%  ion channels - 5%  nuclear receptors - 2%
  12. Target Identification  Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease.  Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease.  Compounds are then identified that have various interactions with the drug targets that
  13. Cellular & Genetic Targets  involves identification of the target receptors or enzymes whereas for some biologic approaches the focus is at the gene or transcription level.  Drugs usually act on the targets, which are associated with disease.
  14. Genomics  The study of genes and their function.  exploit the findings from the sequencing of the human and other genomes to find new drug targets.  Based on 5 or 10 linked proteins per gene, proposes that the number of potential drug targets may lie between 5,000 and 10,000.
  15. Proteomics  It is also at the protein level that disease processes become manifest, and at which most (91%) drugs act.  Therefore, the analysis of proteins (including protein- protein, protein-nucleic acid, and protein ligand interactions) will be utmost importance to target discovery.  Target identification with proteomics is performed by comparing the protein expression levels in normal and diseased tissues.
  16. Bioinformatics  It plays a key role in various stages of the drug discovery process including  target identification  computer screening of chemical compounds and  pharmacogenomics  Can compare the entire genome of pathogenic and non-pathogenic strains of a microbe and identify genes/proteins associated with pathogenism
  17. Target Prioritization/Validation.  To select targets most likely to be useful in the development of new treatments for disease, researchers analyze and compare each drug target to others based on their association with a specific disease and their ability to regulate biological and chemical compounds in the body.  Tests are conducted to confirm that interactions with the drug target are associated with a desired change in the behavior of diseased cells.  Research scientists can then identify compounds that have an effect on the target selected.
  18. Lead Identification.  A lead compound or substance is one that is believed to have potential to treat disease.  Laboratory scientists can compare known substances with new compounds to determine their likelihood of success.  Leads are sometimes developed as collections, or libraries, of individual molecules that possess properties needed in a new drug.  Testing is then done on each of these molecules to confirm its effect on the drug
  19.  Find a promising molecule that could become a drug  Ways to find a lead compound o Nature – bacteria, molds, plant extracts o De Novo – scientists can also create molecules from scratch – computer modeling o High throughput screening – test thousands of compounds against the target to identify any that might be promising o Biotechnology – scientists can genetically engineer living systems to produce disease-fighting biological molecules
  20. Lead discovery • Identification of small molecule modulators of protein function • The process of transforming these into high- content lead series. Synthesis and Isolation • Separation of mixture • Separation of impurities • In vitro chemical synthesis • Biosynthetic intermediate
  21. Combinatorial Chemistry  Rapid synthesis of or computer simulation of large no. of different but structurally related molecules • Search new leads • Optimization of target affinity & selectivity. • ADME properties • Reduce toxicity and eliminate side effects Assay Development • Used for measuring the activity of a drug. • Discriminate between compounds. • Evaluate: • Expressed protein targets. • Enzyme/ substrate interactions.
  22. High Throughput Screening • Screening of drug target against selection of chemicals. • Identification of highly target specific compounds.
  23. Lead Optimization.  Lead optimization compares the properties of various lead compounds and provides information to help biopharmaceutical companies select the compound or compounds with the greatest potential to be developed into safe and effective medicines.  Often during this same stage of development, lead prioritization studies are conducted in living organisms (in vivo) and in cells in the test tube (in vitro) to compare various lead compounds and how they are metabolized
  24.  Optimization o Alter the structure of lead candidates to improve properties o can make it less likely to interact with other chemical pathways in the body, thus reducing the potential for side effects  “analogues” of the initial leads can be made and tested  The biologists test the effects of analogues on biological systems  Chemists take this information to make additional alterations that are then retested by the biologists
  25.  Early safety tests o Lead compounds go through a series of tests to provide an early assessment of the safety. o Scientists test Absorption, Distribution, Metabolism, Excretion and Toxicological (ADME/Tox) properties, or “pharmacokinetics,” of each lead.  Successful drugs must be: o absorbed into the bloodstream, o distributed to the proper site of action in the body, o metabolized efficiently and effectively, o successfully excreted from the body and o demonstrated to be not toxic.  Help researchers prioritize lead compounds early in the discovery process.  ADME/Tox studies are performed in living cells, in animals and
  26. Preclinical  Conversion of drug candidate to a drug product for human clinical trials  Lab and animal testing to determine if the drug is safe enough for human testing  Testing the lead compounds extensively to determine if they should move on to testing in humans  Scientists carry out in vitro and in vivo tests.  Scientists try to understand how the drug works and what its safety profile looks like.
  27. In-vitro  In vitro profiling:  Biochemical assays (e.g. enzyme activity assays) Cell culture assays (e.g. cancer cell lines) Isolated tissue assays (e.g. mucosa model)
  28. Pharmacological & Toxicological approach  Pharmacology - Drug action:  Behaviour and reaction Physiology Histopathology  Toxicology:  Acute toxicity Subchronic toxicity Tissue specific toxicity Tolerability
  29. THE DRUG DEVELOPMENT PROCESS Development Discovery Development Approximately 10–15 years from idea to marketable drug Preclinical studies Clinical studies CHEMISTRY/ PHARMA- COLOGY IND* PHASE I PHASE II PHASE III NDA** PHASE IV Search for active substances Toxicology, efficacy studies on various types of animals Regulatory review Efficacy studies on healthy volunteers Clinical studies on a limited scale Comparative studies on a large number of patients Regulatory review Continued comparative studies*Investigational New Drug Application for permission to administer a new drug to humans 50–150 persons 100–200 patients 500–5,000 patients Registration, market introduction **New Drug Application Application for permission to market a new drug KNOWLEDGE LEVEL KNOWLEDGE LEVEL 2–4 YEARS 2–6 MONTHS 3–6 YEARS 1–3 YEARS TIME SPAN Early Clinical

Hinweis der Redaktion

  1. 1.Candidate drug emerges from a drug discovery programme. Candidate must complete a series of evaluations of its potential safety and efficacy and must be amenable to mass production.for each drug completing the pathway,5000-10000 are evaluated in the discovery phase
  2. There are various ways of illustrating the R&D process – this is one. We see, among other things, how knowledge about a drug increases during the course of the process, but that upon market introduction, there is still a great deal to be learned about how the drug works in the body. Developing a new drug is a complex and costly process. If everything goes according to plan, a new drug will be ready approximately ten years after the work was first begun. We are working to shorten this time to eight years. Pharmaceutical companies are constantly striving to shorten the time from idea to finished pharmaceutical product. At the same time, the demands on documentation continue to rise.