Introduction to Medicinal Chemistry PDF

INTRODUCTION TO MEDICINAL CHEMISTRY JHON RAPHAEL M. JIMENEZ, RPh, MSPharm Pharmaceutical and Medicinal Organic Chemistry TOPIC OUTLINE 1. Discuss historic overview and evolution of medicinal chemistry. 2. Define organic pharmaceutical chemistry. 3. Define Quantitative Structure-Activ...

INTRODUCTION TO MEDICINAL CHEMISTRY JHON RAPHAEL M. JIMENEZ, RPh, MSPharm Pharmaceutical and Medicinal Organic Chemistry TOPIC OUTLINE 1. Discuss historic overview and evolution of medicinal chemistry. 2. Define organic pharmaceutical chemistry. 3. Define Quantitative Structure-Activity Relationship 4. Enumerate the functional groups involved in organic chemistry. DRUGS OF ANTIQUITY  Shen Nung (2735 BC)  Ch’ang shang, Ma huang  American Indians  Chaulmoogra fruit  Brazil  Ipecacuanha root Ma huang Chaulmoogra fruit  South American Indians  Coca leaves  Greek Apothecary  Opium, squill, hyoscyamus, viper toxin, Cu, Zn ores, Fe Ipecacuanha root Coca leaves sulfate, Cadmium oxide MIDDLE AGES  Basic studies in chemistry and physics shifted from the Greco- Roman to the Arabian alchemist  Paracelsus glorified Sb as cure-alls in the belief that chemicals could cure diseases 19th CENTURY: AGE OF INNOVATION AND CHEMISTRY  From finding new medicaments from vast world of plants to finding the AI that accounted for their pharmacologic properties  1805 – Morphine extracted from poppy by Serturner (not widely recognized until 1817, when he reported of 100 mg gave symptoms of severe opium poisoning to himself and three companions)  1810 – Organon der rationellen heilkunde published by Hahnemann on his unproven principle, similia similibus curantur (like cures like, homeopathy) opposing Galen’s theory. Therapeutic doses had to be minute as illness renders patient highly sensitive to drug.  1816 – Isolation of Emetine from Ipecacuanha by Pierre-Pelletier  1820 – Purification of caffeine, quinine and colchicine  1826 – Mass production of pharmaceutical natural product – Pelletier’s factory processed Emetine hydrochloride 150,000 kg of Cinchona bark annually produce 3600 kg of Quinine sulfate, an antimalarial compound  1845 – Adolph Kolbe synthesize Acetic Acid  1878 – Concept of a biological receptor formulated by British pharmacologist, John Langley Quinine sulfate  1886 – First alkaloid was synthesis, Coniine from hemlock  1897 – Ehrlich described Side Chain Theory, germicidal capability of a molecule depends on its structure, particularly its sidechains, which can bind to disease-causing organisms  1898 – First mass- produced synthetic drug, Aspirin by Bayer  20th CENTURY AND PHARMACEUTICAL INDUSTRY  Rise of synthetic chemotherapeutic agents  Gerhard Domagk  Prontosil (2,4-diaminobenzene- 4-sulfonamide) – Effective on Gram (+) bacterias  1929 – Discovery of penicillin by Alexander Fleming  1940 – Bacteriostatic action of sulfonamide-like drugs  PSYCHOPHARMACOLOGIC AGENTS AND ERA OF BRAIN RESEARCH  Discovery of chlorpromazine – single most important Chlorpromazine breakthrough in psychiatric treatment  Discovery of antidepressant effect of Iproniazid Imipramine  Imipramine - first dibenzazepine (Tricyclic Iproniazid antidepressant)  Fluoxetine – first commercially successful SSRI ($1 Billion)  Chlordiazepoxide, diazepam and meprobamate – serendipity Fluoxetine ENDOCRINE THERAPY AND STEROID  Epinephrine – first pure hormone to be isolated  1904 - Henry Dale discovered oxytocin  1914 – Edward Kendall isolated thyroxine from thyroid gland  1921 – Frederick Banting and Charles Best discovered insulin  Humulin (Eli Lily) – first genetically engineered drug approved by US FDA  Symlin (2005) – for Type 1 Diabetes Mellitus  Inhaled insulin (2006)  ENDOCRINE THERAPY AND STEROID  1930 – Russell Marker was able to convert diosgenin to progesterone (acid labile)  1950 – Carl Djerassi synthesized Norethindrone (first orally active contraceptive steroid)  1956 – John Rock – Progesterone Progesterone Norethindrone + Norethindrone (Norminest®)  1980 – Mifepristone – abortion pill  1994 – Mifepristone + Misoprostol  Morning-after pill  AKA Plan B  Emergency contraceptive Mifepristone + Levonorgestrel Misoprostol  Levonorgestrel  ANESTHETICS AND ANALGESICS  First use of synthetic organic chemical  Horace Wells – Dentist who administered nitrous oxide during tooth extraction  Crawford Long used ether as an anesthetic agent Crawford Long  William Morton – gave the first successful public demonstration of surgical anesthesia (1846) Ether dome  Chloroform was used as anesthetic agent at St. Bartholomew’s Hospital  HYPNOTICS AND ANTICONVULSANTS  Laudanum – induce sleep  Bromides, chloral hydrate, paraldehyde, urethane and sulfenal  1864 – Adolph Von Beyer synthesized 5,5-diethylbarbituric acid Phenobarbital (Luminal®)  Bayer Pharm Company introduced Phenobarbital (Luminal®)  Modification of the barbituric acid molecule led to the development of Hydantoins  Phenytoin (Dilantin®) – 5,5- diphenylhydantoin Phenytoin (Dilantin®) LOCAL ANESTHETICS  1860 – Albert Niemann isolated cocaine (Erythroxylon coca)  Carl Koller (”Coca Koller”)  Found that cocaine numbed the tongue  First to use cocaine for topical anesthesia in ophthalmological Erythroxylon coca surgery  Richard Willstater determined the structure of cocaine and atropine  Benzocaine, procaine, tetracaine and lidocaine  Structural analogues of cocaine  DRUGS AFFECTING RENAL AND CARDIOVASCULAR FUNCTION  1775 – Willian Withering discovered Digitalis purpurea was beneficial to those suffering from abnormal fluid buildup  1841 – E. Humolle and T. Quevenne isolated digitoxin  1929 – Sydney Smith isolated digoxin  DRUGS AFFECTING RENAL AND CARDIOVASCULAR FUNCTION  1973 – Akira Endo  Discovered the first anticholesterol drug  Compactin (Mevastin) derived from Penicillium citrinum Akira Endo Compactin (Mevastin)  1978 – Merck discovered a substance nearly identical to Endo’s and named Lovastatin (Mevacor®)  First FDA-approved statin  Atorvastatin (Lipitor®)  ANTINEOPLASTIC AGENTS  Sulfur mustard (WW1) and nitrogen mustard (WW2) → Leukemia therapy  George Hitchings and Gertrude Elion developed 6-mercaptopurine  First effective leukemia drug Mercaptopurine Cisplatin  1893 – Cisplatin  Inorganic; gold standard against new medicines are compared  Carboplatin – 2nd generation  1963 – Moeroe E. Wall and Masukh C. Wani discovered Paclitaxel (Taxol) Carboplatin Paclitaxel (Taxol)  Pacific Yew Tree (Taxus brevifolia) → European Yew Tree (Taxus baccata) ORGANIC PHARMACEUTICAL CHEMISTRY  Study of carbon-based medicinals  A scientific discipline at the intersection of chemistry and pharmacy involved with designing, synthesizing and developing pharmaceutical drugs.  Medicinal chemistry involves the identification, synthesis and development of new chemical entities suitable for therapeutic use.  Pharmaceutical chemistry is focused on quality aspects of medicines and aims to assure fitness for the purpose of medicinal products.  It also includes the study of existing drugs, their biological properties and their Quantitative Structure-Activity Relationships (QSAR) QUANTITATIVE STRUCTURE- ACTIVITY RELATIONSHIP  It is a strategy of the essential importance for chemistry and pharmacy, based on the idea that when we change a structure of a molecule then also the activity or property of the substance will be modified. REQUIRED READINGS Please read the article through the link given: https://www.pharmacologicalsciences.us/medicinal-chemistry- 2/the-history-of-medicinal-chemistry.html NOTE: Quiz next meeting.