HISTORY and EVOLUTION OF MEDICINAL CHEMISTRY 2019_copy
Page 1: Introduction to Medicinal Chemistry
Source: Foye's Principles of Medicinal Chemistry (2013)
Page 2: Topic Outline
Background
Drugs of Antiquity
Middle Ages
19th Century: Age of Innovation & Chemistry
20th Century & the Pharmaceutical Industry
Page 3: Developments in Medicinal Chemistry
Medicinal Classes of Drugs
Old Drugs as Targets for New Drugs
Molecular Imaging
The Next Wave in Drug Discovery: Genomics
Combinatorial Chemistry and High Throughput Screening
Page 4: Historical Background
The evolution of medicinal chemistry driven by:
Ideas and knowledge from previous scientists
Tools that enhance contemporary knowledge
Alfred Burger's Contributions:
Two types of investigators in medicinal chemistry:
Prophetic logic scientists interpreting key experiments effectively.
Chemists varying the chemical structure of active compounds to develop new drugs.
Page 5: Drugs of Antiquity
Ancient civilizations contributed to pharmacology:
Chinese, Hindus, Mayans, Mediterranean Peoples:
Compiled by Emperor Shen Nung as Pharmacopeia.
Active principles derived from:
Ch'ang shang: Alkaloid, anti-malarial.
Ma Huang: Ephedrine, China, Anti-asthmatic.
Chaulmoogra Oil: Treatment for Leprosy from American Indian ipecacuanha root.
Coca Leaves: Cocaine used by South American Indians, also for hallucinogenic mushrooms.
Greek Apothecary Shops: Herbs like Opium and metallic drugs.
Page 6: The Middle Ages
Chemistry studies transitioned from Greco-Roman traditions to Arabian Alchemists (13th - 16th centuries).
Paracelsus promoted the use of Antimony and its salts in elixirs as universal cures due to the belief in the power of chemicals to heal.
Page 7: 19th Century - Age of Innovation & Chemistry
Expansion in chemistry knowledge led to an extended herbal pharmacopoeia.
Key advances:
A. Lavoisier's work refined chemical analysis.
Adolphe Kolbe, 1845: Synthesized acetic acid (CH₃COOH)
Pierre Berthelot, 1856: Synthesized methane.
Transition from pharmacognosy to physiologic chemistry.
Page 8: Advances in Drug Isolation
Shift towards identifying active ingredients rather than entire crude plants.
Key isolations:
Morphine (F. Serturner, 1803): First major isolated drug.
Ipecacuanha (P. Pelletier, 1816): Isolated emetine.
Purification of Caffeine, Quinine, and Colchicine (P. Pelletier, 1820).
Page 9: Development of Pharmaceutical Industry
Digitalis: Used for edema by W. Withering.
Cocaine: Isolated by Albert Niemann (1860) and Physostigmine derived from Calabar Bean.
Growth in organic chemistry led to the formation of the pharmaceutical industry by the late 19th century.
Page 10: 20th Century & the Pharmaceutical Industry
Development of synthetic chemotherapeutic agents to combat diseases from protozoa and spirochetes.
Prontosil (G. Domagk): First synthetic antibacterial agent effective against gram-positive infections.
Action observed by Woods & Fildes (1940): Notable example of counteraction between stimulatory and inhibitory chemical properties.
Page 11: Antibacterial Discoveries
Discovery of Penicillin (1929) by Alexander Fleming revolutionized antibacterial treatment.
Subsequent refinement by Howard Florey and Ernst Chain improved its antibacterial potency and reduced toxicity.
Page 12: Developments in Medicinal Classes of Drugs
Focus on:
Psychopharmacologic agents and brain research.
Endocrine therapy and steroids.
Anesthetics and analgesics.
Hypnotics and anticonvulsants.
Drugs affecting renal and cardiovascular function.
Anticancer agents.
Page 13: Psychopharmacologic Agents and Brain Research
Use of stimulants (e.g., amphetamines) and sedatives to manage mental health conditions.
Chlorpromazine (1950): First antipsychotic drug synthesized by Charpentier.
Henry Laborit noted its effects in humans.
Page 14: Breakthroughs in Antipsychotic Treatment
Chlorpromazine (Thorazine): Marked significant advances in psychiatric treatment.
Discovery of antidepressant effects of Iproniazid led to the development of MAO-inhibitor antidepressants (e.g., Phenelzine, Tranylcypromine).
Page 15: Antidepressant Developments
Imipramine (1957) by Ciba-Geigy: First tricyclic antidepressant, leading to further development of antidepressants.
Connection established between mood elevation via monoamine neurotransmitter activity and treatment efficacy.
SSRIs developed in the late 1980s starting with zimenidine; however, it was toxic.
Page 16: SSRIs and Financial Success
R,S-Fluoxetine (Prozac): First psychotropic agent to exceed $1 billion annually.
Random discovery led to effective anxiolytics and a series of benzodiazepines (e.g., Diazepam, Meprobamate).
Page 17: Bioassays in Drug Development
Bioassays measure potency through effects on living cells/tissues.
Foundations laid by Paul Ehrlich in the late 19th century.
Page 18: Standardization in Bioassays
Paul Ehrlich's work introduced standardization of reactions of living matter, particularly with diphtheria antitoxin.
Page 19: Advances in Treatment of Psychiatric Conditions
In 1946, Frank M. Burger observed paralysis and relaxation effects of compounds in lab animals, facilitating treatment of anxiety with aminoalkylphenothiazines.
Chlordiazepoxide (Librium, 1960): Marked as a significant anxiolytic treatment.
Page 20: Structural Modifications in Benzodiazepines
Synthesis of more potent benzodiazepines such as Diazepam (Valium, 1963) followed by numerous derivatives providing clinical options.
Page 21: Usage of Benzodiazepines
Benzodiazepines prescribed for anxiety, emotional disorders, sleep disorders, convulsive states, and muscle relaxation.
Page 22: Endocrine Therapy: Hormonal Isolation
Epinephrine: First pure hormone isolated from glands; led to molecular advancements in sympathetic amines.
Techniques facilitated the characterization of various hormones.
Page 23: Notable Discoveries in Endocrine Therapy
Isolation of Thyroxine by Edward Kendall (1914); Cortisone activity discovered in 1950 leading to Nobel Prize.
Page 24: Insulin Discovery and Development
1921: Isolated by Frederick Banting & Charles Best – major achievement in drug discovery, tested in dogs.
Genetic engineering in the 1970s produced synthetic insulin.
Page 25: Advancements in Insulin Production
1978: Genentech and City of Hope produced human insulin using recombinant DNA technology.
1982: Lilly’s HUMULIN became the first FDA approved genetically engineered insulin.
Page 26: Commercial Success of Recombinant Insulin
Recombinant insulin has played a key role in the development of genetically engineered drugs, leading to significant therapeutic advancements.
Page 27: Steroid Hormones in Therapy
Derived from sex glands; used in treatments related to sexual maturity and cancer therapy.
Synthetic modifications have led to anabolic steroids and uses in contraception.
Page 28: Contraception Developments
Norethindrone: First orally active contraceptive steroid due to structural modifications.
Combination of Norethindrone and Progesterone led to the oral contraceptive pill (ENOVID).
Page 29: Social Impact of Oral Contraceptives
Considered one of the 7 wonders of the modern world by The Economist in 1993 for its societal impact on women.
Page 30: Mifepristone and Reproductive Health
Ru-486 (Mifepristone): Adopted in 1988 for fertility control with both antifertility and contraceptive effects.
Page 31: Emergency Contraceptives
Plan B: Contains Levonorgestrel; effective as emergency contraception when taken within three days of unprotected intercourse.
Page 32: Anesthetics Overview
Early synthetic organic chemicals were used for anesthesia (e.g., Nitrous oxide, Ether, Chloroform).
William Morton demonstrated anesthesia on Oct 16, 1846.
Page 33: Morphine and Opium
Morphine, isolated by Fredrick W. Serturner in 1805, marks significant historical discoveries.
Laudanum: Alcoholic opium used for various ailments.
Page 34: Morphine and Heroin
Morphine synthesized in the 1950s; Heroin known for addiction.
Synthetic opioids such as OxyCodone and Methadone explored for addiction management.
Page 35: Opioid Addiction and Receptors
Opiate addiction classified as medical conditions; identified three opioid receptors (mu, kappa, delta) impacting pharmacology.
Page 36: Research on Opioid Receptors
Development of radioreceptor binding assays to study opioid receptor activity.
Identified classes of endogenous opioid peptides: Enkephalins, Endorphins, Dynorphins.
Page 37: Early Hypnotics and Anticonvulsants
Historical use of alcohol and opium extracts as sleep-inducing agents; early sedatives identified.
Page 38: Barbiturates
Phenobarbital: Introduced by Bayer in 1938 for hypnotic and anticonvulsant applications.
Phenytoin synthesized for antiseizure effects without sedation.
Page 39: Early Anticonvulsants
Summary of early examples of hypnotics and anticonvulsants, including structures of Phenobarbital and Phenytoin.
Page 40: Local Anesthetics
Origin traced to cocaine; development of various local anesthetic derivatives.
Page 41: Renal and Cardiovascular Drugs
Used to treat ischemia, CHF, arrhythmias.
Digoxin derived from foxglove, critical for treating heart conditions.
Page 42: Advances in Cardiac Glycosides
Isolation of digoxin; statins as crucial cholesterol-lowering medications.
Page 43: Statin Development
Lipitor as a leading-selling drug; research advancements led to the identification of statins as pivotal in cholesterol management.
Page 44: Discovery of Statins
Akira Endo’s discovery of compactin; Merck's development of Lovastatin exemplified innovation in drug discovery.
Page 45: Historical Context of Anticancer Agents
Use of chemical warfare agents led to the discovery of effective antitumor drugs.
Page 46: Development of Anticancer Agents
6-Mercaptopurine as the first effective leukemia drug through rational drug design methodologies.
Page 47: CISPLATIN Introduction
Cisplatin: Origin, significance against various cancers, landmark discoveries in the 1960s.
Page 48: Continued Advancements in Cancer Treatment
Development of Carboplatin and Paclitaxel (Taxol) showcasing progress in oncological pharmacotherapy.
Page 49: Commercial Viability of Taxol
Mechanisms of Taxol leading to its market success and effectiveness in treating multiple forms of cancer.
Page 50: Conclusion
Recap of the historical advancements in medicinal chemistry that foster innovation and subsequent drug development.