Medicinal Chemistry & Drug DiscoveryPowerPoint PresentationMedicinal ChemistrySlide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Medicinal Chemistry FolkloreSlide 15Slide 16Slide 17Drug Discovery One way to “discover” drugsSlide 19Slide 20Slide 21Slide 22Structure-Activity Relationships (SARs)Slide 24Example of SARSAR General Structure of Antimicrobial AgentsSlide 27Slide 28Slide 29BioisosterismSlide 31Slide 32Slide 33Slide 34Slide 35Slide 36Bioisosterism allows modification of physicochemical parametersSlide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 48Slide 49Slide 50Slide 51Slide 52Slide 53Slide 54Slide 55Slide 56Slide 57Slide 58Slide 59Slide 60Slide 61Slide 62Slide 63Slide 64Slide 65Slide 66Slide 67Slide 68Slide 69Medicinal Chemistry &Drug DiscoveryDr. Peter WipfDepartment of ChemistryUniversity of Pittsburghhttp://ccc.chem.pitt.edu/wipf/index.htmlUniversity of Pittsburgh Center for Chemical Methodologies & Library Developmenthttp://ccc.chem.pitt.edu/wipf/Courses.html • Survey of current drugs • Drug discovery challenges • Methods to identify new leads • Case studies from industry • Forward chemical genetics - reverse pharmacologyMedicinal ChemistryThe science that deals with the discovery or design of new therapeutic agents and their development into useful medicines.It involves:• Synthesis• Structure-Activity Relationships (SAR)• Receptor interactions• Absorption, distribution, metabolism, and excretion (ADME)2003 Blockbusters at the Drugstore (US/Worldwide; out of ~$500b)Lipitor (Pfizer) cholesterol $6.8/10.3 billion (66%)Zocor (Merck) cholesterol $4.4/6.1 billion (72%)Zyprexa (Eli Lilly) antipsychotic $3.2/4.8 billion (72%) Norvasc (Pfizer) blood pressure $2.2/4.5 billion (40%) Procrit (J&J) anemia $3.3/4.0 billion (83%)Prevacid (TAP) ulcers $4.0/4.0 billion (100%)Nexium (AstraZeneca) ulcers $3.1/3.8 billion (82%)Plavix (BMS-Sanofi) blood thinner $2.2/3.7 billion (59%)Seretide (GSK) asthma $2.3/3.7 billion (62%)Zoloft (Pfizer) depression $2.9/3.4 billion (85%)Epogen (Amgen) anemia $3.1/? billion (?%) Celebrex (Pfizer) arthritis $2.6/? billion (?%)Source: IMS Health, March 2004NNHOFOHOHOHOLipitorCH3OOOH3CH HHO OHZocorNHNSONCH3O CF3PrevacidSeretideNHNSNNCH3CH3ZyprexaNNCF3H3CSOOH2NCelebrexNHCH3ClClZoloft• HClNexiumNorvascPlavixNMeOSONN)2 Mg2+OHHN(CH2)6O(H2C)4PhHOHOOHCO2HClNSCO2MeHSO4-HNCO2EtMeO2CONH2Cl“Big Pharma” Drug Discovery in the 21st CenturyThe Problem: The pharmaceutical industry is short of new drugs. In the 2nd part of the 20th century, about 50-60 new drugs (NCEs) were approved by the FDA every year. In contrast, in 2002, a historical low of 18 NCEs were approved (in 2001, 24 NCEs, in 2000, 27 NCEs, in 2003, 21 NCEs). Conversely, research costs for a new drug are estimated to be in the $1-1.5 Bi. range. Considering all high-profile failures in recent drug discovery, this figure is unlikely to drop substantially.Source: Wall Street J. 11/21/2003“…gloom around the pharmaceuticals company..”Source: Wall Street J. 2/24/2004Wallstreet (and companies) are looking for a scapegoat..”Drug Industry's Big Push Into Technology Falls Short. Testing Machines Were Built To Streamline Research -- But May Be Stifling It“A decade ago, pharmaceutical companies announced a revolutionary new way of finding drugs. Instead of relying on scientists' hunches about what chemicals to experiment with, they brought in machines to create thousands of chemical combinations at once and tested them out with robots. The new technology was supposed to bring a flood of medicines to patients and profits to investors.Today, some leading chemists are calling the effort an expensive fiasco.Machines churned out chemical after chemical that didn't produce useful results. And chemicals that seemed promising often turned out to have big flaws that traditional testing might have caught earlier on. Some drugs couldn't dissolve in water or be turned into pills, for example.Critics believe these problems help explain the pharmaceutical industry's drought of new products. "That's the secret of why they're spending billions of dollars and getting nothing," says James Hussey, a former Bristol-Myers Squibb Co. manager who now leads biotech company NeoPharm Inc.…..”In Search of New Leads…..The decline in the number of new drugs is based, among other reasons, on the current high therapeutic standard in many indications, focusing research on chronic diseases such as coronary heart, Alzheimer’s, arthritis, cancer, and AIDS, as well as the enhanced regulatory requirements for efficacy and safety of new drugs.A lead can be characterized as a compound that has some desirable biological activity, not extremely polar or lipophilic, and not contain toxic or reactive functional groups. Often, molecular weight (<350) and lipophilicity (log P < 3) are considered the most obvious characteristics of a drug-like lead.The lead should also have a series of congeners that modulate biological activity, indicating that further structural modification will improve selectivity and potency.Estimates of the number of possible drug molecules average 1040. Incontrast, the number of seconds since the Big Bang is only 1017.If 10,000 chemists were to prepare 1 compound each per second, it would take 10,000,000,000,000,000,000,000,000,000 years to finish the job. Why Is It So Difficult to Make Drugs?Drug Discovery ParadigmChemistry-drivendrug discovery -back to the future?Currently:Biology-drivendrug discoveryWhere Did (Do) Our Drugs Come From?New drugs from old poisonsThe reductionist approach to medicine began with the isolation of opium alkaloidsOHOHNHOCH3OOHNOCH3OCH3OCH3OCH3OHNHOCH3codeineheroinmorphineMedicinal Chemistry FolkloreEarliest medicines ~ 5100 years agoChinese emperor Shen Nung - book of herbs, Pen Ts’aoCh’ang Shan - contains alkaloids; used today in the treatment of malaria and for feversMa Huang - contains ephedrine; used as a heart stimulant and for asthma. Now used by body builders and endurance athletes because it quickly converts fat into energy and increases strength of muscle fibers.Modern therapeutics:Extract of foxglove plant, cited by Welsh physicians in 1250. Used to treat dropsy (congestive heart failure) in 1785 Contains digitoxin and digoxin; today called digitalisAt least a quarter of all prescriptions dispensed in the US and UK contain, as