Week 1

• Drug discovery is a process that has been around for centuries, with the first recorded instance being the use of serum anti-toxins in the 1890s.
• In the late 19th and early 20th century, various illnesses such as Diptheria, tetanus, cholera, etc. were common and fatal, which were generated by injecting these toxins into an animal, usually a horse.
• Wellcome Laboratory was the first laboratory in the UK, established by Henry Wellcome and Silas Burroughs in 1880.
• In 1889, it was proposed that the pancreas was important with regards to diabetes, as dogs with pancreas removed displayed similar symptoms.
• In 1921, insulin was extracted from dog’s pancreas.
• Soon after, insulin was extracted from cattle and in January 1922, the first person was injected with insulin (animal substance).
• The discovery of insulin led to the standardisation and marketing of therapeutic substances, which came into force in 1925 and covered only these substances: Sera and vaccines, Pituitary preparations, Insulin, Salvarsan.
• In 1909, the British Medical Association analysed multiple preparations that could be purchased, which were commonly used talcolm powder.
• In 1928, Alexander Fleming discovered Penicillin, which was significant during WWII.
• Penicillin was mass produced in the USA in 1941, leading to the Penicillin Act in 1942, which was concerned with purity and rationing.
• The Medicines Act in 1968 replaced the previous two acts.
• Thalidomide tragedy led to changes in the licensing system, including manufacturer/premises/drug, regulation of packaging and labelling, and regulation of advertising.
• Phenotype (Empirical) involves testing large numbers of random compounds for desirable effects in a biological test system, with the mode of action/mechanism generally unknown.
• Target (Rational) involves understanding the target (receptor/enzyme/ion channel) effects.
• Multiple small scale trials with severe familial hypercholesterolemia showed Lovastatin effective in lowering plasma LDL-C.
• All cause mortality was reduced by 42% in the Scandinavian Simvastatin Survival group study, due to a reduction in coronary deaths.
• The Lovastatin Trial tested Lovastatin against cholestyramine and probucol.
• The Lovastatin Study Group III (1988) paper, published in JAMA, showed that Lovastatin reduced the primary endpoint of all cause mortality.
• The Scandinavian Simvastatin Survival group study, published in Lancet in 1994, showed that statins reduced mortality.
• Patients were recruited for the Scandinavian Simvastatin Survival group study with a history of angina or MI.
• If LDL-C is present, cholesterol synthesis is inhibited by Lovastatin.
• The primary goal in drug discovery is for patient benefit, improved patient outcomes.
• Lovastatin was approved by the FDA in 1987.
• Patients were recruited for the Lovastatin Study Group III with a history of angina or MI.
• Propanolol is an example of early drug design, where the action of isoprenaline provided evidence for selectivity, with the task being to alter the compound from an agonist to antagonist.
• Experimental design is key to ensuring data validity and rigor.
• Understanding of key pathological mechanisms is beneficial and essential for target identification and validation.
• Statins reduced the primary endpoint of all cause mortality in the Scandinavian Simvastatin Survival group study.
• Phenotypic and rational drug design have both been shown to be successful in the discovery of drugs.
• All cause mortality was reduced by 42% in the Lovastatin Study Group III, due to a reduction in coronary deaths.
• Compactin was found to lower serum cholesterol in monkeys, dogs, and hens.
• Enzyme substrate HMG CoA as a target Hydroxymethylglutarate is water soluble and can be broken down with other pathways.
• In 1981 Brown and Goldstein discovered that LDL receptors were responsible for the uptake of LDL, also patients with familial hypercholesterolemia lacked functional LDLr.
• Compactin development was terminated by Sankyo in 1979.
• Discovery of statins HMG CoA reductase activity/expression was upregulated in Compactin-treated animals.
• Hypothesis Antibiotics inhibit many enzymes and so fungi would produce antibiotics which could inhibit HMG CoA.
• Merck heard rumours that Compactin caused lymphoma in dogs in 1980 and the lovastatin project was halted and further toxicology studies initiated.
• Screening 3800 fungi (phenotypic drug design) resulted in the discovery of citrinin which inhibited HMG CoA and lowered plasma cholesterol in rats.
• • 1985 Brown and Goldstein discovered that apoB-100 was the apolipoprotein responsible for transport of cholesterol in HDL.
• Merck Research Laboratories isolated mevinolin (lovastatin) from fungus Aspergillus terreus in 1980.