Lecture 15_What is Medicinal Chemistry PDF

Fall 2023: PHRM601 Principles of Drug Action Lecture # 15 Welcome! Part III: Fundamentals of Medicinal Chemistry / Course Introduction (What is a Drug? History of MedChem/Nomenclature)...

Fall 2023: PHRM601 Principles of Drug Action Lecture # 15 Welcome! Part III: Fundamentals of Medicinal Chemistry / Course Introduction (What is a Drug? History of MedChem/Nomenclature) Keykavous Parang [email protected] Office: Suite 262, 9401 Jeronim Office hour: By appointment  Course Introduction: Why Study Medicinal Chemistry? The importance of drug chemistry to the practice of pharmacy is “logical”  If drugs are chemicals, and  If Pharmacists are drug experts,  Then Pharmacists are the chemical experts of the health care team.  Needs to understand the physical and chemical properties of the medicinal agents that are dispensed.  Why do pharmacists need to know about Medicinal Chemistry and Drugs To help the practicing pharmacist to better understand the clinical properties of these compounds (potency, duration of action, selectivity) To anticipate the properties of new agents that appear on the market To anticipate formulation problems To anticipate potential adverse drug interactions with other drugs as the result of serum protein binding or metabolism Drug metabolism: To predict the consequences of drug-drug interactions, drug- food interactions, and herbal-drug interactions to explain a patient's adverse responses to drug regimens  Faculty Interactions & Resources Office hours will be set up by appointment (in person or on Zoom). Please email 48 h in advance to schedule a meeting. Complete pre-class activities and assigned work. Participate in Interactive discussions in the class. Poll Everywhere, quizzes 4  Study Skills Please make every effort to be on time in the class. Read the assigned materials prior to coming to class. Study with other pharmacy students in your class. Stay on top of the material. Clarify any muddy points with instructors, tutors, study groups, etc. Work the practice exercises from the text. Read the textbooks Check Canvas 24 hours earlier for any updates in the slide deck.  Learning Resources Required Resources 1. Victoria F. Roche, S. William Zito, Thomas L. Lemke, David A. Williams. Foye's Principles of Medicinal Chemistry 8th ed., Lippincott Williams & Wilkins, 2019. http://libproxy.chapman.edu/login?url=http://pharmacy.lwwhealthlibrary.com/book.aspx?bookid=758 This textbook covers topics covered in this course as well as in the remaining Medicinal Chemistry and Pharmacology courses in the curriculum. 2. Review of Organic Functional Groups (Introduction to Medicinal Organic Chemistry), Thomas L. Lemke, 5th edition, 2011 Lippincott Williams & Wilkins. You are required to know the functional groups of drugs. (Just for practice some problem/guided reading) http://pharmacy.lwwhealthlibrary.com.libproxy.chapman.edu/book.aspx?bookid=824 This textbook is required for those students who want to refresh their organic chemistry background.  Optional Learning Resources 1. An Introduction to Medicinal Chemistry, Graham L. Patrick, 6th edition, 2017, Oxford University Press. 2. Basic Concepts in Medicinal Chemistry, Second Edition, Marc W Harrold and Robin M. Zavod, 2018, ASHS.  Evaluation of Student Performance Classroom Attendance and Participation Poll Everywhere and quizzes Integrated Exams. Factual recall and Analysis. Comprehension of concepts and application.  Grading Grade Distribution Pre-Class Activity (Examples below) 10% - Assignments - Poll Everywhere (MCQ) - Worksheets - Quizzes In Class Activity 10% - Attendance, Poll Everywhere - Participation - Group discussion - Quizzes Exams 80% – Exam 1 (20%) – Exam 2 (20%) – Exam 3 (20%) – Exam 4 (20%) Final Exam (includes cumulative questions)  Exam Schedule & Questions Examination Date Question Item Covered Material methods/type Time s + Therapeutic Relevance 36 +12 Fundamentals of 10/23/20 Exam 2 Medicinal Chemistry MC/online 23 (Lecture 15-16) Fundamentals of Medicinal Chemistry + Tools in 11/27/20 48 Medicinal Chemistry: Drug Exam 3 MC/online Design and Optimization 23 (Lecture 17-24) Exam 4 New material (Lectures#: 25, 12/13/20 Cumulative 26, 27, 28) +All course MC/online 24+12+12 Final Exam materials taught (Cumulative) 23 *Parang (Lectures 15-24): cumulative questions = 12 # Nauli +Dr. Sam (Lectures 1-14): cumulative questions = 12 Course Tour  Medicinal Chemistry Drug sicochemical Property of Drug-1 TargetDrug Discovery Development & Optimization Drug Functional Group (FG) Class Acidity and Basicity of FG Enzymes Optimization of Drug Anticancer Absorption Drugs Receptor sicochemical Property of Drug-2 Chemical basis of Drug Metabolism Nucleotide Drug target interaction based Forces involved in Drug-Receptor drugs Interactions Target access Antiviral - Salt and Solubility - Chirality Discovery & Design Peptide/Protein based drug Combinatorial & Parallel Chemistry Use of Computers in Drug Design (Molecular Modelling, QSAR, AI) Fundamentals of Medicinal Chemistry Tools in Medicinal Chemistry Tools in Medicinal Chemistry  Today’s Class: Learning Objectives Define terminology: “ Drug, Therapeutic Index, Discovery, Optimization, Development, and Medicinal chemistry”. Differentiate between Drug and Poison. Explain the role of medicinal chemistry in Pharmacy Practice. Describe nomenclature of organic compounds/drugs. Describe major contributions to the history of medicinal chemistry.  Definition of Drug Compounds that interact with a biological system to produce a biological response. Tea, coffee, cocoa, coke, pepsi (all contain caffeine) Nicotine in cigarette Alcohol Morphine (low dose Painkiller, at high dose a poison which kills by suffocation) Snake venom (Death) LSD (hallucination) Sugar (sense of taste) Penicillin (antibiotic) Herbicide, pesticide Junk foods and fizzy drinks ( high concentrations of certain amino acids in nervous system, hyperactivity in children)  Drug: Compounds, which interact with a biological system to produce a biological response Definition of a “Drug” as regulated by the FDA Effective for advertised/approved condition Safe Stable On the shelf and in vivo Deliverable and bioavailable Must be absorbed and delivered to site of action Available: By synthesis or by isolation from natural sources Novel: Patentable (This is requirement for the industry, not the FDA)  Drugs names Normally three names are associated with a drug: Trade or proprietary name (e.g., Lipitor) Generic name, or nonproprietary name (e.g., atorvastatin) A specific chemical name for the active ingredient (e.g., [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1- heptanoic acid, calcium salt (2:1) trihydrate) Over-the-counter (OTC) https://www.drugbank.ca/drugs/DB01076  No “perfect” drug “Good” drugs Penicillin (Antibiotic) But cannot kill all known bacteria, resistant bacteria Morphine (Analgesic) But also causes addiction, respiratory depression “Bad” drugs Heroin Effective painkiller Diamorphine But is also a drug of choice for treating patients dying of cancer Pharmacist Alert *Quantitative measure for “Good” drug: Therapeutic Index A measure of the drug’s beneficial effects at a low dose versus its harmful effects at a high dose ―Ratio of the drug dose level leading to toxic effects in 50% of cases studied (TD50) to the dose level leading to maximum therapeutic effects in 50% of cases studied (ED50). TD50 / ED50 ―Alcohol = 10, Cannabis = 1000 (toxic in chronic use, dizziness, blurred vision, impaired memory).  A high therapeutic index means that there is a large safety margin between beneficial and toxic doses No drug is totally safe, depending on the dose. ―A useful drug can be poison at high doses or chronic use. ―A poison can be medicine at low doses (arsenic used as an antiprotozoal agent, ACE inhibitors based on snake venom) Everything is a poison, nothing is a poison. ―The dose level of a compound determines whether it will act as a medicine or as a poison (taking 100 aspirin, 9 kg of spinach, a bottle of whisky, …) Dose of drug in plasma Dose is plotted of drug in the in plasma is horizontal axishorizontal plotted in the while the axis percentage of individuals while the (animals or humans) that responds percentage or shows of individuals a toxic (animals effect is represented or humans) in or that responds theshows vertical axis. a toxic effect is represented in the vertical axis.  Medicinal Chemistry Medicinal Chemistry is defined as an interdisciplinary science situated at the interface of life sciences (such as biochemistry, pharmacology, molecular biology, immunology, pharmacokinetics, and toxicology) on one side and chemistry-based disciplines (such as organic chemistry, physical chemistry, crystallography, spectroscopy, and computer-based information technologies) on the other. http://pharmacy.lwwhealthlibrary.com.libproxy.chapman.edu/content.aspx?sectionid=50009952&  What is Medicinal Chemistry? It is the organic chemistry of drug design, development, and action It can explain how the chemistry of a drug defines drug-receptor interactions It can describe how the chemistry of a drug defines its absorption, transport, and distribution properties It can explain how the chemistry of a drug defines the metabolic transformation of drugs into other chemicals It is used for designing prodrugs, predicting toxicities, and predicting drug interactions. Medicinal chemistry relates to the design and production of compounds that can be used in medicine for the prevention, treatment, or cure of human and animal diseases Medicinal chemistry covers three critical steps: A discovery step consists of the identification and production of new active substances usually called lead compounds. Leads can originate from synthetic organic chemistry and or from natural sources or from biotechnological processes. An optimization step that deals mainly with the synthetic modification of the lead structure in order to improve potency, selectivity, and lessen toxicity. Its characteristics are in the establishment and analysis of structure-activity relationships (SAR). A development step consisting of the optimization of the synthetic route for bulk production, modification of the pharmacokinetic, and pharmaceutical properties of the active substances to render it suitable for clinical use. This may cover optimization of properties associated with: Chemical formulation, Solubility, Elimination of unpleasant taste or irritation, and Reduction of pain at the site of injection. https://www.future-science.com/doi/10.4155/fmc.11.135  Define Drug Targets and their importance to the pharmaceutical industry Drug targets are large molecules - macromolecules Drugs are generally much smaller than their targets Drugs interact with their targets by binding to binding sites Binding sites are typically hydrophobic hollows or clefts on the surface of macromolecules Binding interactions typically involve intermolecular bonds Most drugs are in equilibrium between being bound and unbound to their target Functional groups on the drug are involved in binding interactions and are called binding groups (Pharmacophore) Specific regions within the binding site that are involved in binding interactions are called binding regions  Drug Targets Lipids Cell membrane lipids Proteins Receptors Enzymes Transport proteins Structural proteins (tubulin) Nucleic acids DNA RNA Carbohydrates Cell surface carbohydrates Antigens and recognition molecules harmacist Alert Real Examples of Roles of Medicinal Chemists in Drug Discovery by Inhibiting Drug Targets 1. Cancer Chemotherapy:  Drugs like Imatinib (Gleevec) were developed through medicinal chemistry to specifically target cancer cells by inhibiting specific proteins (BCR-ABL tyrosine kinase) responsible for uncontrolled cell growth. 2. Cardiovascular Medications:  Drugs like Statins (e.g., Atorvastatin) were designed to lower cholesterol levels in the blood, by inhibiting HMG-CoA reductase as a crucial enzyme in the biosynthesis of cholesterol in the liver, reducing the risk of heart disease. harmacist Alert Real Examples of Roles of Medicinal Chemists in Drug Discovery by Inhibiting Drug Targets 3. Antiviral Drugs:  Nucleoside analogs like acyclovir that mimic the structure of natural nucleosides (the building blocks of DNA and RNA). These analogs could potentially interfere with viral replication. 4. Psychiatric Medications:  Compounds like Serotonin Reuptake Inhibitors (e.g., Fluoxetine/Prozac) were designed to treat depression and anxiety disorders by selectively inhibiting the reuptake of serotonin in the brain, leading to increased levels of the neurotransmitter in the synaptic cleft.  Targeting Diseases Priority for the Pharmaceutical Industry Can the profits from marketing a new drug outweigh the cost of developing and testing that drug? Questions to be addressed Is the disease widespread? (e.g. cardiovascular disease, ulcers, malaria) Does the disease affect the first world? (e.g. cardiovascular disease, ulcers) Are there drugs already on the market? If so, what are their advantages and disadvantages (e.g. side effects) Can one identify a market advantage for a new therapy?  Drug Discovery Process Time and Money 50,000 - 5,000,000 compounds are often screened to find a single drug >1,000 “hits” 12 “leads” 6 drug candidates 1 drug Discovery & Preclinical trials Clinical trials: Phase I, Phase II, Phase III Up to 15 years $1.3 to 2.5 billion  Origins of Medicinal Chemistry (Good to Know) 1. Early investigations of natural products 1.1. In the so-called pre-scientific era Natural products having a history as folk remedies were in use. For example, opium, belladonna, cinchona bark, etc. Many drugs originally used as folk remedies, nowadays, have been abandoned. 1.2. In the late eighteenth and early nineteenth centuries, chemical experimentation ultimately led to its use in the discovery of new drugs. In 1853, Henry: Conceived the idea that functional groups in natural products might be modified by chemical reagents. N He heated morphine with methyl iodide, hoping to convert the alkaloid to codeine. He obtained, however, a new substance of the quaternary salt of morphine. HO O H OH  In 1898, the first commercially available semisynthetic morphine derivative (ethyl ether) was introduced as a cough sedative in preference to codeine or other opiates. Meanwhile, diacetylmorphine (heroin) was introduced as a safer pain reliever than morphine. It quickly became popular throughout the world. Four years passed before its addictive properties of heroin were recognized. Laws were later passed by governments to restrict its use. 1.3. Developments of MC Leading to Various Medicinal Classes of Drugs During the 1840s, the first use of synthetic organic chemicals was introduced for anesthesia during tooth removal, such as nitrous oxide, ether, and chloroform. In 1864, barbituric was synthesized as a useful hypnotic.  In 1875, salicylic acid was introduced as a possible cure for typhoid fever. It was found to be an effective antipyretic. In 1899, Aspirin was marketed as an antipyretic without the unpleasant side effects. This indicated that the chemical structures from natural products were changed into better drugs. Medicinal Chemistry began. 2. Fast Development from 1900’s to 1960’s 1920’s~1930’s: Anesthetics, Hypnotics, and Analgesics were used extensively. In research, efforts were made to “pharmacophore”, the “structure- function relationship” concept during the investigation.  After 1930’s: The development of new drugs was speeded greatly with the close combination of Medicinal Chemistry and Experimental Pharmacology. Theory of antimetabolite was formed by using metabolic products as lead compounds. Discovery of penicillin (1928) and isolation (1940) which is the first antibiotic is an epoch-making achievement. Afterward, tetracycline, streptomycin, chloramphenicol, erythromycin were introduced one after another. In 1940’s, the first drug used for treating cancer as a biological alkylating agent was nitrogen mustard, which began tumor chemical therapy. After 1950’s, aging disease, cerebrovascular and cardiovascular diseases became first reason for human death. New drug design based on enzymes or receptors as drug targets.  In 1960’s, oral steroidal contraceptive agents were discovered. Corticosteroids have become important drugs. In 1964, the first β-Adrenergic blocking agent, Propranolol, was marketed. In 1979, Nifedipine, Calcium Channel Blocker was marketed. In 1981, Captopril, Angiotensin angiotensin-converting enzyme (ACE) Inhibitor was launched. 2000-2023, Targeted Cancer Therapy (kinase inhibitors), Immunotherapy (Abs), AI Future of Medicinal Chemistry: New drugs will be discovered or invented by investigating human genomics, human disease genomics, proteomics, and using tools such as artificial intelligence.  Key Facts to Remember! What is Medicinal Chemistry and its steps? What are Drug targets and how do you differentiate different drugs as safe based on their therapeutic index? Importance of MedChem for Pharmacists and Drug Discovery Functional group nomenclatures for regular functional groups, such as COOH, OH, SH, COOR, ROR, Ph, R-X, etc.