Week One Introduction PDF

Introduction to PHM2006 Medicinal Chemistry Dr. Yun Bai  Assessment Component/ method % weight Assignment 15 Quiz 15 Midterm exam 35 Final exam 35 Topics 1 Introduction to drug and drug development-I...

Introduction to PHM2006 Medicinal Chemistry Dr. Yun Bai  Assessment Component/ method % weight Assignment 15 Quiz 15 Midterm exam 35 Final exam 35 Topics 1 Introduction to drug and drug development-I Introduction to drug and drug development-II 2 Drug Discovery: Finding a Lead -I Drug Discovery: Finding a Lead-II 3 Drug Design: Optimizing Target Interactions -I Drug Design: Optimizing Target Interactions -II 4 Drug Design: Optimizing Access to Target-I Drug Design: Optimizing Access to Target-II 5 Computers in Medicinal Chemistry-I Computers in Medicinal Chemistry-II 6 Case Study I ( Drug Design) Midterm 7 Pharmacokinetics and Drug Metabolism-I Pharmacokinetics and Drug Metabolism-II 8 Drug and Drug Targets: An Overview Drug and Drug Targets: Enzymes 9 Drug and Drug Targets: Receptors-I Drug and Drug Targets: Receptors-II Drug and Drug Targets: Signal Transduction 10 Drug and Drug Targets: Other Target Sites Drugs and Drug Targets: Nucleic Acids 11 12 Small molecule drug discovery; concepts of combinatorial and parallel synthesis Small molecule drug discovery; concepts of combinatorial and parallel synthesis 13 Get the drug to the market Get the drug to the market 14 Overview of the course Introduction to Drug History of Medicines - The 20th Century In 1901, the average life expectancy was 47 years. By the year 2001 it had risen 30 years to 77 years.  Drugs Any chemical substance that affects living tissue The chemicals synthesized within the body (e.g., hormones) The chemicals not synthesized in the body (i.e., xenobiotics, from the Greek xenos, meaning "stranger"). Poisons: Drugs that have almost exclusively harmful effects. ✓ Inorganic poisons: Arsenic, lead etc. ✓ Toxins: Poisons of biologic origin, i.e., synthesized by plants or animals The effects caused by the drug can be exploited to alleviate the results of illness The drug rarely cures “The dose makes the poison” (Paracelsus 1493–1541)  Poisons or Drugs? Lethal poisons can be the starting point for the development of useful drugs. Example: Curare : Mainly composed of the toxin D-tubocurarine ✓ alkaloid poisons originated from plant extract. ✓ Native people of south America use to tip their arrows for hunting ✓ Tubocurarine chloride acts as an antagonist for the nicotinic acetylcholine receptor (nAChr) ✓ Compounds based on the tubocurarine structure (the active principle of curare) are used in surgical operations to relax muscles ✓ Safer curare derivatives, such as rocuronium and pancuronium, have superseded d-tubocurarine for anesthesia during surgery.  Drugs Legal Definition Brief Medico-legal definition: Articles (other than food) intended for use in the diagnosis, mitigation, treatment, or prevention of disease or affect the structure and function of the body of man or other animals  Drug Classes We classify drugs primarily four ways Pharmacological effect (for example analgesics, antipsychotics, antihypertensives, anti-asthmatics, and antibiotics) Chemical structure （for example penicillins, barbiturates, opiates, steroids） Target system Target molecule （for example, anticholinesterases are drugs which act by inhibiting the enzyme acetylcholinesterase. )  Nomenclature of Drug Drug have three or more names. Code number or code designation Chemical name. Proprietary, brand or trade name Nonproprietary, generic, official, or common name  Drug Nomenclature Type Responsible Example Agency Chemical The guide of International 7-chloro-2-methylamino-5- Union of Pure and Applied phenyl-3H-1,4- Chemistry (IUPAC) benzodiazepine-4-oxide Nonproprietary United States Adopted (generic) name Name (USAN) council chlodiazepoxide Sponsored by, (not capitalized) APhA, AMA, USP Proprietary Selected by the company Librium (Trade) name marketing the drug  Traditional pharmaceutical sectors: Chemical-based drugs : chemical synthesis Extraction or isolation from biological sources ( Biologics) Biopharmaceuticals : A class of therapeutic agents produced by modern biotechnological techniques, like recombinant DNA, protein engineering, and hybridoma technologies etc. (macromolecules )  Summary of Part 1 Drugs can be classified by their pharmacological effect, their chemical structure, their effect on a target system, or their effect on a target structure. Clinically useful drugs have a trade (or brand) name, as well as a recommended international non-proprietary name. Most structures produced during the development of a new drug are not considered for the clinic. They are identified by simple codes that are specific to each research group. Traditional Small Molecular Drug Discovery and Development  History of Drug Development Plants or Natural Product Plant and Natural products were source for medical substance Example: foxglove used to treat congestive heart failure Foxglove contain digitalis and cardiotonic glycoside Identification of active component Accidental Observations Penicillin is one good example Alexander Fleming observed the effect of mold Mold(Penicillium) produce substance penicillin Discovery of penicillin lead to large scale screening Soil microorganism were grown and tested Streptomycin, neomycin, gentamicin, tetracyclines etc.  Penicillin Discovery The first chemical compound found to have antibiotic properties was penicillin, which was identified by Alexander Fleming in 1928 Dr. Fleming noted that a mold called Penicillium notatum had contaminated his Petri dishes. Some factor in the Penicillium mold that not only inhibited the growth of the bacteria but, might be harnessed to combat infectious diseases. Enhancing with mutation-causing X-rays and filtration, ultimately producing 1,000 times as much penicillin as the first batches from Penicillium notatum  Example One : Natural Aspirin - 1853 The ancient Greek physician Hippocrates and Dioscorides both wrote about the pain relieving ability of a plant. The bark of a white willow tree grew in the Mediterranean. The active ingredient was identified more than 2,000 years later in 1853… and called salicylic acid. Because of the difficulty of taking salicylic acid by mouth, acetylsalicylic acid, popularly known as aspirin, was developed synthetically (man-made). It is the most widely used drug in the world.  Example Two: Cocaine, the First Anesthetic - 1884 (“Numbing agent”) The Natives of the Andes used to chew coca leaves for its medicinal effects and also to increase endurance. Cocaine is the active ingredient in the leaves. Carl Koller, a Viennese surgeon in 1884 used it as the first local anesthetic which revolutionized surgery and dentistry. Because of its harmful properties when abused, other synthetic substitutes were Procaine (Novacain®) and Lidocaine. Modern Drug Discovery and Development  Drug Discovery phase: identification of a new chemical entity as potential therapeutic agent Development phase: compound is tested for safety and efficacy for one or more clinical indications ,and insuitable formulation and dosage form Preclinical development: non-human studies ( e.g. toxicity testing, pharmacokinetics analysis , formulation) Clinical development: the selected compound is tested for efficacy and safety in volunteers and patients  Drug Discovery : Finding a Lead Choosing a disease Pharmaceutical companies tend to concentrate on developing drugs for diseases which are prevalent in developed countries and aim to produce compounds with better proper- ties than existing drugs. Chooing a drug target A molecular target is chosen which is believed to influence a particular disease when affected by a drug. The greater the selectivity that can be achieved, the less chance of side effects. Identififying a bioassay A suitable bioassay must be devised which will demon- strate whether a drug has activity against a particular target. Bioassays can be carried out in vitro or in vivo, and usually a combination of tests is used. Mechanism Based Drug Development Mechanism based drug design: When the disease process is understood at the molecular level and the target molecules are defined Drug can be designed specifically to interact with the target molecule Target: Molecular recognition site to which drug binds Target may be protein molecule A receptor Enzyme Transport molecule Ion channel  Mechanism Based Drug Development Today, most important developments in medical science typically begin in laboratories, such as the discovery of specific new biological molecules, processes, or pathways, or innovative applications of existing knowledge. Target Identification and Validation : CHOOSE A MOLECULE TO TARGET WITH A DRUG Drug Discovery: FIND A PROMISING MOLECULE (A “LEAD COMPOUND”) THAT COULD BECOME A NEW MEDICINE Lead Optimization: ALTER THE STRUCTURE OF LEAD CANDIDATES TO IMPROVE PROPERTIES NATIONAL INSTITUTES OF HEALTH, OFFICE OF TECHNOLOGY TRANSFER  Summary of Part 2 Traditional drug discovery and development. Modern drug discovery and development Medicinal Chemistry  Medicinal Chemsitry Medicial Chemistry concerns the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds at the molecular level Involves: Synthesis Structure-Activity Relationship (SAR) Receptor interactions Absorption, distribution, metabolism, and excretion (ADME)  Medicinal Chemistry Covers the Three Stages Discovery step: Involving Choice of therapeutic target ( receptor, enzyme ) Indentification or discovery and production of new active substances ( Lead compound) Interacting with selected targets Optimization step: Deal with improvement of lead compound. Incrrease in potency, selectivity Decrease toxicity Development stage: continuation of improvement of PK properties  Objective of Medicinal Chemisitry Drug discovery: finding a lead Choose a diseas Choose a drug target Identify a bioassay Find a lead compound Isolate and purify the lead compound if necessary Determine the structure of the lead compound if necessary  Objective of Medicinal Chemistry Drug design Identify structure-activity relationship (SARs) Identify the pharmacophore Improve target interactions ( Pharmacodynamics) Improve pharmacokinetic properties  Objective of Medicinal Chemistry Drug Development Patent the drug Carry out preclinical trials Design a manufactring process Carry out clinical trials Register and market the drug Medicinal chemistry includes synthetic and computational aspects of the study of existing drugs and agents in development in relation to their bioactivities ( understanding a SAR or tailoring of drug)  What is combinatorial chemistry Combinatorial chemistry is a technique by which large numbers of different but structurally similar molecules are produced rapidly and submitted for pharmacological assay This technique uses the same reacton conditions with the same reaction vessels to produce a large range of analogues Technique invented in the late 1980s and early 1990s to enable tasks to be applied to many molecules simultaneously  QuantitatIve Structure Activity Relationship (QSAR) QSAR is a mathematical relationship in the form of an equation between the biological activity and measurable physiochemical parameters QSAR attempts to identify and quantify the physicochemical properties of a drug and to see whether any of these property has an effect on the drugs biological activity Medicinal Chemistry Related Courses Pharmacology: The study of substances that interact with the living system through chemical/biochemical processes specially by binding with regulatory molecules and activating or inhibiting normal body processes Pharmacon (Drug) Pharmacology Logus (Study of)  Pharmacokinetics What body does to the drug? How body affect the drug? Characteristics such as Absorption Distribution Biotransformation Elimination Certain terms that will be employed and used while studying pharmacology and therapeutics are: Absorption, % protein binding, Kd (dissociation rate constant), AUC, T ½, elimination rate constant, onset of action, clearance, etc.  Pharmacodynamics What drug(s) does to the body (How drug produces its effect in the body) Study of effects of drugs on various organs, organ systems, tissues or cells Study of the biochemical and physiological effects of drugs and their mechanisms of action Adverse Drug Reaction (ADR) Therapeutic Effect toxicity Three phases of drug action  Pipeline of Drug Development On average, it takes at least ten years for a new medicine to complete the journey from initial discovery to the marketplace, with clinical trials alone taking six to seven years on average. The average cost to research and develop each successful drug is estimated to be $2.6 billion. The Food and Drug Administration (FDA) Monitors drug studies for safety and efficacy before a drug is marketed in the United States Also monitors the drug after approval for sale to the public, for any adverse effects – called Post Marketing Surveillance Recalls drugs if they have proven dangerous within public safety