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How Drugs are Discovered and Developed

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Carleton University
CHEM 1004
Gerald Buchanan

How Drugs are Discovered and Developed ● Drugs through the ages ◦ 1844/1863: Nitrous oxide as anesthetic ◦ 1899: Bayer selling Aspirin worldwide ◦ 1942: Mustine introduced as first chemotherapeutic ◦ 1953: Acetaminophen launched in U.S.; Tylenol brand arrived in 1955 ◦ 1961: Birth control pill introduced ◦ 1957: Thalidomide introduced ▪ Resulting birth defects caused massive overhaul of evaluation system ▪ Discovered that stereochemistry (handedness) of thalidomide was critical ▪ drug was sold as 50% R, 50% S (“racemic”) ▪ one hand caused birth defects, other cured morning sickness ● Ways to Control Stereochemistry: internal control, chiral auxiliary, chiral reagent, chiral catalyst, chiral solvent ● 2001 Nobel Prize in Chemistry for Catalytic Asymmetric Synthesis: William S. Knowles, Ryoji Noyoriand K. Barry Sharpless ● Rational Drug Design ◦ How to develop a small organic molecule into a drug ▪ small organic molecules make up about 68% of all new drugs (32% large biological molecules) ▪ 1. Understand biology of illness ▪ 2. Understand biochemistry of illness ▪ 3. Find molecule to disrupt/promote biochemistry in vitro ▪ 4. Animal testing (a.k.a. in vivo testing) ▪ 5. Human testing and development ▪ 6. Bring to market ◦ The IDEAL DRUG ▪ A PILL ● must not be destroyed in digestive system ● must cross intestinal membrane and get to target tissue(s) in body ● must be reasonably soluble in water and fat ▪ ONCE- or TWICE-PER-DAY DOSING ● half-life of 12 to 24 hours ● not metabolized too quickly or too slowly ● effective at reasonable concentration ● Biology and Biochemistry ◦ Understand biochemistry of illness ◦ Long and complicated process ◦ Don’t need to completely understand ◦ Identify potential drug target(s) – enzymes ▪ What makes a target good? ● different from other known enzymes ● similar enzymes can lead to drug acting on those enzymes too = side effects ◦ an enzyme is a protein that catalyzes a specific chemical reaction ◦ most enzymes are at least 100 amino acids long ◦ Some diseases are harder to treat then others because of slow or rapid progression ● Once biochemical target is determined and selected, need an in vitro test ◦ modern tests use only enzyme, not whole cells or tissues – simple, fast but hides potential problems ◦ whole cell assays are much slower (days instead of minutes) but reveal or hint at dangerous off-target effects right away (this saves $) ◦ since late 1970s/early 80s the emphasis has been to make more compounds and increase speed of in vitro testing ◦ works well when research diseases with simple biochemistry ◦ current research is looking at diseases with extremely complex biochemistry - this we should return to whole cell assays 5 6 ● Drug companies have libraries of compounds (10 to >10 ); compounds come from many different sources ◦ compounds made in the lab during previous research projects and stored ◦ new compounds made by rapid, semi-random chemistry (combinatorial chemistry/combi- chem) ◦ “secondary metabolites”/“natural products” – compounds made by an organism to give it an evolutionary advantage but not absolutely required for survival (primary metabolism) ◦ isolated from plant, animal, or microbe ◦ many older drugs were natural products or modified natural products ● In Vitro Testing ◦ Screen selected compounds from library against target ▪ Screening is iterative process ▪ Identify "hits", analyze chemical structures and repeat screen with similar compounds from library ● Medicinal Chemistry ◦ After repeated screenings, take best compounds and start making new but similar molecules and test them ◦ Make molecule more “drug-like” ▪ certain types of structures are guaranteed to have “off-target” effects or be rapidly metabolized ▪ Small changes in molecular structure can have incredible biological effects ◦ Need a molecule that has desired effects and no off-target effects/side effects ▪ off-target effects often impossible to predict ◦ Lipinski's Rule of Five ▪ Not more than 5 H-bond donors ▪ Not more than 10 H-bond acceptors ▪ A molecular mass of 500 Daltons or less ▪ An octanol-water partition coefficient of not greater than 100,000 ▪ Abilify: Schizophrenia, Bipolar Disorder, Adjunct to Unipolar Depression ● 1 H-bond donor ● 5 H-bond acceptors ● 448 Daltons ● Partition coefficient: 31,600 ▪ Lipitor: Lowers blood cholesterol ● 4 H-bond donors ● 6 H-bond acceptors ● 559 Daltons ● Partition coefficient: 500,000 ▪ Viagra: Treats erectile dysfunction ● 1 H-bond donor ● 4 H-bond acceptors ● 475 Daltons ● Partition coefficient: 79 ▪ Amphotericin B: Antimycotic ● 13 H-bond donors ● 18 H-bond acceptors ● 924 Daltons ● Partition coefficient: 6.3 ● X-Ray Crystallography and Computer Modelling ◦ Crystals are solids where molecules and their constituent atoms are arranged in a repeating pattern ▪ these patterns can be simple or very complex ◦ when a beam of x-rays are shone on a crystal, the x-rays are diffracted by atoms heavier than hydrogen ▪ produces a pattern on the detector and through complex calculations (by a person or a computer) this can be converted to a 2D or 3D arrangement of atoms ◦ Isolate biological target, grow a crystal of it, perform X-ray diffraction ◦ gives 3D structure of target ◦ put structure into computer, see where molecules fit inside ◦ use this info to help design molecules to be tested ● Optimization ◦ Between human decisions and computer simulation data, cycle is repeated until something optimal is found ● Animal Testing ◦ Begin live animal testing ▪ choice of animal depends on illness ▪ can make animal have or mimic illness ◦ usually start small and move up ◦ common animals: mice, rats, rabbits, guinea pigs, dogs (beagles), pigs ◦ Looking For: Is compound effective?, Is animal healthy after treatment? How is compound metabolized? “Pharmacokinetics” ◦ Different animals may give conflicting results ◦ Drug candidate may fail animal testing and new candidates may have to be developed– back to medicinal chemistry ● Process Chemistry ◦ If compound is doing well, we will need much mor
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