A Brief History of Drug Discovery PDF

A Brief History of Drug Discovery CH456 Medicinal Chemistry © 2025 James H. Gerlach What is a drug? A drug is a substance which may have medicinal, intoxicating, performance enhancing or other effects when taken or put into a human body or the body of another animal and is n...

A Brief History of Drug Discovery CH456 Medicinal Chemistry © 2025 James H. Gerlach What is a drug? A drug is a substance which may have medicinal, intoxicating, performance enhancing or other effects when taken or put into a human body or the body of another animal and is not considered a food or exclusively a food. In pharmacology, a drug is "a chemical substance used in the treatment, cure, prevention or diagnosis of disease or used to otherwise enhance physical or mental well-being". Drugs may be prescribed for a limited duration, or on a regular basis for chronic disorders. Recreational drugs are chemical substances that affect the central nervous system (CNS), such as opioids or hallucinogens. They may be used for perceived beneficial effects on perception, consciousness, personality and behaviour. Some drugs can cause addiction and/or habituation. Selected Drugs from Early Recorded History (1 of 2) China 1st documented drug treatment – China 3000 BCE A plant, Ma Huang (Ephedra vulgaris), was used to treat coughs. The active component is ephedrine. A diastereomer, pseudoephedrine (Sudafed), is used as a decongestant. Pseudoephedrine can be converted in methamphetamine. Chemical Structures of MDMA and Related Compounds Physical Harm and Dependence of Various Drugs Selected Drugs from Early Recorded History (2 of 2) Greece Hippocrates (ca. 480 – 360 BCE) – humoral medicine Four elements of the world (air, earth, fire and water) are linked to four humours of the body (black bile, blood, phlegm and yellow bile). Remained a major influence on medical practice and teaching until well into the 1800s. Morphine usage mentioned by Theophratus (372 – 287 BCE). Codeine Family Bayer Heroin Hydrochloride (Heroin) Mrs. Winslow’s Soothing Syrup (Morphine) Cocaine Toothache Drops (Cocaine) Cigarettes (Nicotine) Cocarettes (Coca and Nicotine) Middle Ages to Modern Times (1 of 6) Caffeine Found in coffee (Coffea arabica), caffeine is a stimulant and diuretic. Introduced to Europe through Constantinople (modern Istanbul) in the 1500s. Theobromine is found in cacao seeds (Theobroma cacao). Theophylline is found in tea (Camellia sinensis). Middle Ages to Modern Times (2 of 6) Arsenic anti-infectives Arsenic anti-infectives are organic compounds containing at least one arsenic atom. Arsenic trioxide (As2O3) was used as treatment of trypanosomes in the 1800s. e.g., sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), leishmaniasis (various species of Leishmania) Sodium arsanilate or atoxyl was developed specifically for trypanosome treatment. Paul Ehrlich (1854–1915) developed arsphenamine or “606”. True structure of arsphenamine became a point of controversy in the 1970s. In 2005 the structure was confirmed to be a cyclic oligomer of three or five identical subunits. Arsphenamine undergoes metabolism in the body to form the actual antiprotozoal. Middle Ages to Modern Times (3 of 6) Sulfonamides (Sulfa drugs) were the first antimicrobial drugs. They are synthetic agents containing a sulfonamide group. They are competitive inhibitors of dihydropteroate synthetase (DHPS), an enzyme involved in folate synthesis. They are bacteriostatic agents but do not kill bacteria directly. i.e., They inhibit growth and reproduction of bacteria. Prontosil Rubrum) Middle Ages to Modern Times (4 of 6) History of sulfa drugs Work began at Bayer AG, at that time a component of the huge German chemical trust IG Farben. It was believed that because coal-tar dyes bind preferentially to bacteria and parasites, they might be used to target harmful organisms in the body. In 1932, a team led by physician/researcher Gerhard Domagk found a red dye that had remarkable effects on stopping some bacterial infections in mice. They published the results in 1935. Prontosil, as Bayer named the new drug, was the first medicinal compound that could effectively treat a range of bacterial infections inside the body. Middle Ages to Modern Times (5 of 6) Prontosil is a prodrug. It is active against bacteria in live animals but not in vitro. Metabolized in the body to release a smaller, colourless, active sulfanilamide. The “Elixir Sulfanilamide” disaster. Sulfanilamide had been first synthesized in 1906, and the patent had expired. In the late 1930s, many forms of sulfa drugs were created and marketed without any testing being required. The S. E. Massengill Company created “Elixir Sulfanilamide”. They added raspberry flavouring and 10% diethylene glycol as a solvent. At least 100 people died as a result of ingesting the elixir. This disaster led to the passage in the United States of the Federal Food, Drug and Cosmetic Act in 1938. Middle Ages to Modern Times (6 of 6) Thalidomide A sedative and antiemetic drug developed by the German pharmaceutical company Chemie Grünenthal in 1957 and prescribed to treat morning sickness in 1st trimester of pregnancy. Birth defects From 1960 – 1961, children were born with malformed limbs. Approximately 10,000 children were affected world-wide (115 in Canada). Animal testing Thalidomide was not tested on pregnant animals. Thalidomide is a racemic mixture: (R) enantiomer is effective against morning sickness, (S) enantiomer is teratogenic. The two forms can interconvert in vivo. Thalidomide Enantiomers Thalidomide Update (2012) “Thalidomide maker apologizes 50 years after drug pulled.” – CBC News Sept 1, 2012 “We ask for forgiveness that for nearly 50 years we didn't find a way of reaching out to you from human being to human being.” Harald Stock, CEO of Grünenthal Group Grünenthal has said that it has paid roughly 500 million Euros to victims by 2010. Canadian Thalidomide survivor Paul Murphy called the apology a “good joke” and an “insult”. In 1991, the federal government extended assistance of $7.5 million to the Canadian-born “thalidomiders”. It was a one-time payout of between $52,000 and $82,000 per victim and offered no sustained support. Thalidomide Update (Jan 2015) “Canadian thalidomide survivors say they expect offer this month.” – Globe and Mail Jan 5, 2015 The Conservative government supported an NDP motion on December 1 to support victims of thalidomide and talks are progressing between Ottawa and the Thalidomide Victims Association of Canada. Many victims today say they are fighting a losing battle against pain as their aging bodies cope with the ravages of the drug. The thalidomide group wants Ottawa to make good on its promise to give 95 survivors “full support” by the time Parliament reconvenes January 26, 2016. The group is seeking a lump sum of $250,000 per victim to address immediate needs and $75,000 to $150,000 per person a year depending on the degree of the person’s disability. Thalidomide Update (May 2015) “Thalidomide survivors cheer Ottawa’s new annual pension program.” – Globe and Mail May 22, 2015 Federal government will provide thalidomide survivors with pensions of up to $100,000 a year for the remainder of their lives. Payments are in three levels – $25,000, $75,000 and $100,000 per year. Thalidomide Update (August 2015) “Frances Oldham Kelsey averted a thalidomide tragedy because she wouldn’t be rushed.” – Globe and Mail Aug 14, 2015 Born Jul 24, 1914, in Cobble Hill, BC. Working as a drug reviewer for the FDA,she refused approval for thalidomide. Received an “Award for Distinguished Federal Civilian Service” in 1962. Died on Aug 7, 2015, in London, ON, at the age of 101. Thalidomide in Modern Medicine (1 of 2) Leprosy In 1964, Israeli physician Jacob Sheskin administered thalidomide to a patient critically ill with leprosy with favourable results. The patient had erythema nodosum leprosum (ENL), a painful skin condition. Since 1965, Brazilian physicians prescribe thalidomide as the drug of choice for the treatment of severe ENL. Since 1994, women prescribed thalidomide are required to use two forms of birth control and submit to regular pregnancy tests. Despite this, cases of thalidomide embryopathy continue, with at least 100 cases identified in Brazil between 2005 and 2010. In 1998, the FDA approved the use of thalidomide in the treatment of ENL. In 2010, the WHO stated that it did not recommend thalidomide due the difficulty of controlling its use. Thalidomide in Modern Medicine (2 of 2) Cancer Judah Folkman pioneered studies into the role of angiogenesis (the growth of blood vessels from the existing vasculature) in the development of cancer and in the early 1970s had shown that solid tumors could not grow without it. In 1993, he surprised the scientific world by hypothesizing the same was true of blood cancers (leukemias and lymphomas). In 1994, he published in vivo work showing that thalidomide inhibited angiogenesis. Clinical trials have confirmed its efficacy in treating multiple myeloma, most often when used in combination with other medications. In 2006, the FDA granted accelerated approval for thalidomide in combination with dexamethasone (a fluorinated glucocorticoid) for the treatment of newly diagnosed multiple myeloma patients.