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Development mol drug


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Development mol drug

  2. 2. What is a drug? • Any chemical compound - sugar ??? • Anything which produces a change in the body - an axe ??? • Define by characteristics: 1. use or potential use in diagnosis or treatment of disease 2. selective in their actions
  3. 3. • A substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication recognized or defined by the U.S. Food, Drug, and Cosmetic Act. • A drug is any chemical or biological substance, synthetic or non-synthetic DRUG
  4. 4. SOURCES OF DRUGS Animal insulin (pig, cow) growth hormone (man) Plant digitalis (digitalis purpurea) morphine (papaver somniferum) Inorganic arsenic lithium Synthetic chemical (propranolol) biological – bacteria-(penicillin) biotechnology-RDT- (human insulin)
  5. 5. Why are new drugs needed? UNMET MEDICAL NEED new diseases (AIDS, Alzheimer’s, obesity)  low efficacy (dementia, cancer)  side effects (antidepressants, antipsychotics) downstream health costs; (Alzheimer’s, spinal injury)  cost of therapy; (Interleukins)  costs to individual/country
  6. 6. HISTORY • 1557, Renaissance surgeon conducted first clinical trial unintentionally using turpentine, rose oil, egg yolk to prevent treatment to battlefield wounds ▫ New treatment was more effective. • 1747, James Lind, Father of clinical trails first to introduce control groups in his exp. ▫ Documented that citrus fruits could prevent scurvy. • Concept of study design began in 19th century. ▫ 1863 placebos were used for the first time ▫ 1923 idea of randomization was introduced • 1948 first randomized trial with blinding was conducted by Medical Research Council for use of streptomycin to treat pulmonary tuberculosis • Since 1945, ethical impact of clinical trial gained importance resulting in strict regulations of medical experiments on human subjects • 1947, Nuremberg code • 1964, Declaration of Helsinki (amended in 1975, 1983, 1989,1996,2000,2002,2004)
  7. 7. HISTORY- Regulatory • Earlier drugs and medicines were based on ancient art of pharmacy. • 19th century, pharmaceutical industry came into being. Catalyst Event Sulfanilamide Tragedy Nazi Physicians Trial Thalidomide Tragedy Syphilis Study Regulatory Milestone Food, Drug, and Cosmetic Act- 1938 – concept of testing marketed drugs on human subjects Nuremberg Code-1947- informed consent by subjects Kefauver-Harris Amendments-1962- efficacy tests for new drugs National Research Act-1974- Commission for Protection of Human Subjects for Behavioral and Biochemical Research
  8. 8. HISTORY – regulations cont… • Drug development is lengthy and costly process. • FDA review takes upto 2.5 yrs • 1992- Prescription Drugs User Fee Act – reduced review process from 30 months to 15 months • 1999, founded. • 2006, FDA approves first cervical cancer vaccine, Gardasil in just 6 mnths as a part of FDA’s new priority review system.
  9. 9. Drug Discovery and Development Process The Cost of Drug Discovery and Development  Average cost to discover and develop a new drug = $800 million Average length of time from discovery to patient = 10-15 years Only one NCE (new chemical entity) out of 10,000 leads will make it to launch. Target Identification and Validation Assay Development Lead Generation Hypothesis Generation Candidate Development Commercialization Phase III Submit Global Launch Global Optimization Lead Optimization First Human Dose Phase IA Phase IB/II
  10. 10. DRUG DEVELOPMENT Three phases: Discovery Pre clinical development Clinical
  11. 11. Drug Discovery & Development Identify disease Isolate protein involved in disease (2-5 years) Find a drug effective against disease protein (2-5 years) Preclinical testing (1-3 years) Formulation Human clinical trials (2-10 years) Scale-up FDA approval (2-3 years)
  12. 12. Technology is impacting this process Identify disease Isolate protein Find drug Preclinical testing GENOMICS, PROTEOMICS & BIOPHARM. HIGH THROUGHPUT SCREENING MOLECULAR MODELING VIRTUAL SCREENING COMBINATORIAL CHEMISTRY IN VITRO & IN SILICO ADME MODELS Potentially producing many more targets and “personalized” targets Screening up to 100,000 compounds a day for activity against a target protein Using a computer to predict activity Rapidly producing vast numbers of compounds Computer graphics & models help improve activity Tissue and computer models begin to replace animal testing
  13. 13. High throughput screening (HTS) Structure Activity relationship (SAR) Phase I Phase II Phase III Phase IV Drug Candidate development Toxicology Pharmacokinetics ADME
  14. 14. (A). Drug Discovery I. Choose a disease VI. Market V. Clinical Trials IV. Optimize lead III. Find a lead compound II. Choose a drug target
  15. 15. I. Choosing a Disease • What factors? ▫ Medical ▫ Economic ▫ Geographical Pharmaceutical companies must make a profit to exist Pharmaceutical companies will, therefore, avoid products with too small a market (i.e. a disease which only affects a small subset of the population) Pharmaceutical companies will also avoid products that would be consumed by individuals of lower economic status (i.e. a disease which only affects third world countries) Most research is carried out on diseases which afflict “first world” countries: (e.g. cancer, cardiovascular diseases, depression, diabetes, flu, migraine,
  16. 16. II. Choosing a Drug Target • What are they?  Drug Target = specific macromolecule, or biological system, which the drug will interact with • How are they discovered?  Sometimes this can happen through incidental observation…  From drugs  From chemical messengers  Molecular genetics
  17. 17. Identifying a Drug Target (cont.)  Example: In addition to their being able to inhibit the uptake of noradrenaline, the older tricyclic antidepressants were observed to “incidentally” inhibit serotonin uptake. Thus, it was decided to prepare molecules which could specifically inhibit serotonin uptake. It wasn’t clear that this would work, but it eventually resulted in the production of fluoxetine (Prozac). NH2 N H HO serotonin O HN prozac N N CH3 H3C Imipramine (a classical tricyclic antidepressant) F3C
  18. 18. The mapping of the human genome should help! • Many medicines (and lead compounds) were isolated from plant sources. • Having the genetic code for the production of an enzyme or a receptor may enable us to over-express that protein and determine its structure and biological function. If it is deemed important to the disease process, inhibitors (of enzymes), or antagonists or agonists of the receptors can be prepared through a process called rational drug design. • Plants and natural sources are not likely to provide the cures to all diseases. • In a process called “combinatorial chemistry” large numbers of compounds can be prepared at one time. Combitorial chemistry
  19. 19. • Multiple targets • Choosing the Bioassay In vitro: In an artificial environment, as in a test tube or culture media  High throughput screening  NMR (Nuclear Magnetic resonance) In vivo: In the living body, referring to tests conducted in living animals Ex vivo: Usually refers to doing the test on a tissue taken from a living organism Screening perhaps millions of compounds in a corporate collection to see if any show activity against a certain disease protein HIGH THROUPUT SCREENING:
  20. 20. III. Find a Lead Compound • “lead compound” = structure that has some activity against the chosen target, but not yet good enough to be the drug itself. • Where?  Random screening ▫ Synthetic chemicals: already manufactured by pharmaceutical companies ▫ Natural products: Plants, microbes, the marine world, and animals Pacific yew tree Taxol
  21. 21. III. Find a Lead Compound • Existing drugs ▫ Previously marketed for same disease ▫ Used for other diseases Using Someone Else’s Lead Design structure which is similar to existing lead, but different enough to avoid patent restrictions. Sometimes this can lead to dramatic improvements in biological activity and pharmacokinetic profile. (e.g. modern penicillins are much better drugs than original discovery). Enhance a side effect O N H S O O N H tolbutam ide N H 2S O O H 2N sulphanilam ide (an antibacterial w ith the side effect of low ering glucose levels in the blood and also diuretic activity) (a com pound w hich has been optim ized to only low er blood glucose levels. U seful in the treatm ent of T ype II diabetes.) S N H N O O S O OH 2N C l C hlorothiazide (a com pound w hich has been optim ized to only display diuretic activity.)
  22. 22. III. Find a Lead Compound • Existing drugs • Natural substrate or product ▫ Alter structure: ▫ Use structural similarity to a natural ligand S E ES P E EP P E E + P E S E + S E
  23. 23. III. Find a Lead Compound • Existing drugs • Natural substrate or product • Combinatorial synthesis
  24. 24. III. Find a Lead Compound • Existing drugs • Natural substrate or product • Combinatorial synthesis • Computer-aided design ▫ X-ray crystallography of binding sites ▫ Molecular modeling to design drug Computer-Assisted Drug Design If one knows the precise molecular structure of the target (enzyme or receptor), then one can use a computer to design a perfectly-fitting ligand.
  25. 25. III. Find a Lead Compound • Existing drugs • Natural substrate or product • Combinatorial synthesis • Computer-aided design • Chance : Serendipity • Example: Penicillin discovery • Example: development of Viagra to treat erectile dysfunction N N S O O N N N NH O O viagra (Sildenafil)
  26. 26. III. Find a Lead Compound • Existing drugs • Natural substrate or product • Combinatorial synthesis • Computer-aided design • Chance • NMR Binding Site Protein
  28. 28. 13C NMR C C CHCH CH CH2 CH2 CH3 CH3
  29. 29. CH2 CH3 13C NMR C C CHCH CH CH2 CH3
  30. 30. Protein Optimize epitope
  31. 31. Protein Optimize epitope Optimize epitope
  32. 32. Protein Optimize epitope Optimize epitope Link
  34. 34. H N HO O OH N O O OM e OM e M eO O O Me Epitope A Epitope B
  35. 35. H N HO O OH N O O OM e OM e M eO O O Lead compound
  36. 36. III. Find a Lead Compound • After lead compound is found, but before optimizing… ▫ Isolate ▫ Purify ▫ Structural confirmation
  37. 37. IV. Optimize Lead Compound N OH OH CH 3 R O H R O M e C H 3I C H 3C O C l R O O C H 3 C H 3S O 2C l R S O O C H 3 O LiA lH 4 R H Ether Ester Alkane • Structure-activity relationships (SARs) Alcohol: •Structure-Activity-Relationship (SAR) = How does the activity change as structure is systematically altered? •Identify the “pharmacophore” pharmacophore = the structural features directly responsible for activity •Vary structure to improve interactions with target •This may enable one to prepare a more active molecule •This may allow the elimination of “excessive” functionality, thus reducing the toxicity and cost of production of the active material •This can be done through synthetic modifications Example: R-OH can be converted to R-OCH3 to see if O-H is involved in an important interaction
  38. 38. IV. Optimize Lead Compound 1. Variation of alkyl substituents 2. Variation of chain length ANALOGUE C CH 3 CH 3H 3C van der Waals interactions LEAD COMPOUND CH 3 Hydrophobic pocket
  39. 39. RECEPTOR Unused binding region DRUG RECEPTOR DRUG Extra functional group Drug Extension 3. Extension of structure
  40. 40. Binding Region (H-Bond) Binding Region (for Y) para Substitution Binding site H O Y meta Substitution Binding site O H Y Weak H-Bond Strong H-Bond (increased activity) Variation of Ring Size and Structure 4. Change in substitution pattern
  41. 41. Hydrophobic regions R R R R Ring expansion Variation of Ring Size and Structure 5. Variation in ring size 6. Variation in ring structure H N S
  42. 42. O H NHM e O M e HO O C Ph Cl Drug OH NHM ePh Drug 7. Simplification H NX CH3 X NHM e X NHM e X M e N X NM e X NHM e Introducing rings 8. Rigidification
  43. 43. (B). PRE CLINICAL DEVELOPMENT  Toxicology  Pharmacokinetics  ADME studies Performed in animal models in vitro  in vivo  in silico
  44. 44. TOXICOLOGY Pharmacological effects are same in man as in animals Toxic effect in species will predict adverse effects in man Giving high doses in animals improves predictability to man Systemic toxicology studies Single dose studies Repeated dose studies Reproductive toxicology studies Male fertility Female reproduction & Developmental studies Local toxicity studies Hypersensitivity studies Genotoxicity studies Carcinogenicity studies
  45. 45. ADME STUDIES & pharmacokinetics These studies are carried out to reveal the effects of drug on the body In vitro In vivo In silico
  46. 46. In silico  In silico is an expression used to mean “performed on computer”.  In silico research in drug is thought to have the potential to speed the rate of drug discovery while reducing the need of expensive lab work and clinical trials. APPROACHES: Genomic sequence analysis Analysis of 3D structure of protein Biological pathways analysis and modeling In silico cell analysis of prokaryotic and eukaryotic hosts e.g. E.coli, B.subtilis, yeast etc. To calculate the ADME/Tox properties ,various software are available: C2-ADME TOPKET GLGOP Drug Metrix Bioprint GestroPlus
  47. 47. Real time in-vivo imaging/biophotonic technology • Devp. and devised by xenogen corp.usa • Brand name IVIS IMAGING SYSTEM • Creates image or photo data from intact living animal system to study pharmacological activity • Ensures more efficient utilization of animal models • Effective against in-vivo study of cancer, anti-inflammatory,infectious disease HOW IT WORKS? • Requires transgenic animals as (animal models) • luciferase genes gets incoroporated into other cells of animal (tagged cell) that tag cell is injected into the animals and emit light when activated. Anthrax expressing the lungs & respiratory tract
  48. 48. IND (Investigational New Drug Application) IND- notice of claimed investigational exemption for a new drug must be filed with regulatory body
  50. 50. (C). CLINICAL DEVELOPMENT  Phase I  Phase II  Phase III  Phase 1V A clinical trial is defined as organized research on human beings intended to provide adequate information on the drug use as a therapeutic agent on its safety and efficacy.
  51. 51. A clinical trial may be designed to : • Assess the safety and effectiveness of a new medication or device • Assess the safety and effectiveness of a different dose of a medication than is commonly used • Assess the safety and effectiveness of an already marketed medication or device for a new indication • Assess whether the new medication or device is more effective for the patient's condition than the already used, standard medication or device
  52. 52. Phase 0 • Phase 0 is conducted in accordance with the U.S. FDA’s 2006 Guidance on Exploratory Investigational New Drug (IND) Studies. • Phase 0 trials are also known as human micro dosing studies. • Distinctive features include the administration of single sub- therapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary PK and PD data. • A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect.
  53. 53. Phase I • Phase I trials classically are considered ‘‘first in human’’ studies. • A small (20-100) group of healthy volunteers will be selected. • Used to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug. • Phase I trials include dose-ranging, also called dose escalation studies so that the appropriate dose for therapeutic use can be found. 20-100 in Phase I
  54. 54. Phase II  Phase II trials are performed on larger groups (20-300).  They are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients.  A Phase II trial can last two to three years. Hundreds in Phase II
  55. 55. • Phase II studies are sometimes divided into: • Phase IIA • Phase IIB • Phase IIA is specifically designed to assess dosing requirements (how much drug should be given). • Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).
  56. 56. PHASE III • Also known as therapeutic confirmatory trials • randomized controlled • multicenter trials • on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) • Safety ,drug interactions are accessed on a larger scale • Additional pharmacokinetic data may be obtained. • Phase III trials are the most expensive • time-consuming
  57. 57. NDA (New Drug Application)  The vehicle through which drug sponsors formally propose that the regulatory body approve a new pharmaceutical for sale and marketing.  Form 44  The data gathered during the animal studies and human clinical trials of an Investigational new product become part of the NDA.
  59. 59. Phase IV • Post marketing survelliance • Used to describe the research and studies associated with product safety evaluation after the drug has been approved for marketing. • Pms=Pharmacovigilance+Pharmacoeconomics+Pharmaco epidemiology. • No fix duration
  60. 60. OBJECTIVES OF PMS  Confirm the efficacy and safety profile in large populations during practice  Detect the unknown adverse drug reaction/s  Evaluation of over-dosage and treatments  Identifications of new indications  Evaluation of new formulations, dosages, durations of treatment.  Evaluation in different age groups / types of patients
  61. 61. Development Programme for an NCE PHASE III PHASE IV PHASE I PHASE IPRECLINICAL PHASE II Product Approval (NDA/MAA) Patient studiesEntry to man (IND / CTA) None Healthy subjects Safety and tolerability Genetic toxicity (in vivo) Repeat dose toxicity testing + Bioanalysis / Toxicokinetics Drug Metabolism Reproductive Toxicity Testing (teratogenicity) Patients Small scale efficacy studies Patients Large scale multicentre studies Chronic (long term) toxicity testing + Bioanalysis / Toxicokinetics Reproductive Toxicity Testing (fertility and pre/post natal) Carcinogenicity studies Drug Metabolism Patients Large scale post-marketing studies As required Genetic toxicity (in vitro) Single / repeat dose toxicity studies + Bioanalysis / Toxicokinetics Safety Pharmacology Drug Metabolism Lead candidate Identified Non-clinical
  62. 62. REFERENCES • Gupta S. K; Basic principles of clinical research and methodology • gopher:// guide •
  63. 63. QUESTIONS???
  64. 64. THANK YOU !!