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PHL 616 Drug Discovery & Development First and second lectures By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected] Drug Discovery & Development, Overview A drug target can be a receptor/ion channel, enzyme, hormone/factor, DNA, RNA, nuclear receptor, or other, unidentified, biological entity Once drug targets are identified, they are exposed to a large number of compounds in an in vitro or cell-based assay Compounds that elicit a positive response in a particular assay are called “hits.” Hits that continue to show positive response in more complex models rise to “leads” (lead identification) A selected few of the optimized leads (candidate drugs) are then advanced to preclinical testing and clinical testing and therefore passed along to the product development staff Drug Discovery, Definitions Drug “A chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect” Drugs may be synthetic chemicals, chemicals obtained from plants, microorganisms or animals, or products of genetic engineering Medicine “A chemical preparation, which usually contains one or more drugs, administered with the intention of producing a therapeutic effect” Medicines usually contain other substances (excipients, stabilisers, solvents, etc.) besides the active drug, to make them more convenient to use To count as a drug, the substance must be administered as such, rather than released by physiological mechanisms Many substances, such as insulin or thyroxine, are endogenous hormones but are also drugs when they are administered intentionally Many drugs are not used in medicines but are nevertheless useful research tools The word drug is often associated with addictive, narcotic substances-an unfortunate negative implication that tends to bias opinion against any form of chemical therapy Drug Discovery, Definitions Effects (therapeutic effects) “The desired results of administration of a medication” Side Effects (adverse effects) “Effects that are harmful and undesired, and that occur in addition to the desired therapeutic effects” Indications “The reasons for administering a medication or performing a treatment” Contra-indications “Factors that prevent the use of a medication or treatment (e.g., allergies)” Drug Nomenclature Chemical name represents the exact description of the drug’s chemical composition Generic name (non-proprietary) - simpler than the chemical name and - derived from the chemical name itself - easier to remember Example 1: the chemical name 2-methyl-5-nitroimidazole-l-ethanol is condensed to the generic name metronidazole. The word methylnitro is condensed to metroni and dazole is due to its imidazole ring Example 2: Metoclopramide is the condensed form of the word methoxychloroprocainamide: where Me is retained and th is written as t; chloro is written as clo: and procainamide is written as pramide Brand or trade name (proprietary) is developed by the company requesting approval for the drug and identifies it as the exclusive property of that company. Example 1: Metrogyl® is the trade name for metronidazole. Example 2: Reglan® is the trade name for metoclopramide. Example 3: Amoxil® is the trade name for amoxycillin. Example 4: Celebrex® is the trade name for celecoxib. Drug-Body Interactions Pharmacokinetics Pharmacokinetics (in Greek: "pharmacon" meaning drug, and "kinetikos" meaning putting in motion) The study of the movement of drugs in the body, including the processes of absorption, distribution, localization in tissues, biotransformation and excretion Pharmacodynamics The study of the action or effects of drugs on living organisms Pharmacokinetics What the body does to the drug vs Pharmacodynamics What the drug does to the body Drug Sources Many therapeutic agents originate from natural products Until about 1950, when synthetic chemistry really came into its own as a source of new drugs, most of the pharmacopoeia consisted of natural products, and they continue to be important drug source, e.g. paclitaxel Such ready-made, highly evolved biomolecules are supposed to have a better chance of interacting with selected drug targets than do random synthetic molecules Exploiting such compound library is seen as an attractive strategy which has led to some important therapeutic breakthroughs, such as: The anti-malarial drug artemesinin Immunosuppressants such as tacrolimus [fujimycin or (FK506)] Paclitaxel and other recently introduced anticancer drugs Many therapeutic agents originate from natural products In practice, the theoretical advantages of natural products are balanced by several practical disadvantages: Access to source material in remote places can be troublesome for geographical reasons The continuing availability of the active compound, if it cannot be synthesized on a commercial basis, may be uncertain Purification and structure determination of natural products is often difficult and timeconsuming Many antibiotics originate from microorganisms Fosfomycin is produced by several Streptomyces species Cycloserine is an antibiotic produced by Streptomyces orchidaceous Bacitracin is a polypeptide antibiotic produced by strains of Bacillus subtilis and Bacillus licheniformis Vancomycin is an antibiotic produced by Streptococcus orientalis Benzylpenicillin (penicillin G) is produced by Penicillium chrysogenum Cephalosporins were first obtained from a filamentous fungus “Cephalosporium” The intrinsic antimicrobial activity of natural cephalosporins is low, but the attachment of various groups has yielded drugs of good therapeutic activity and low toxicity Imipenem was discovered in 1980 via a lengthy trial-and-error search for a more stable version of the natural product thienamycin, which is produced by the bacterium Streptomyces cattleya. Thienamycin has antibacterial activity, but is unstable in aqueous solution, so impractical to administer to patients MOA of inhibitors of cell wall synthesis Creation of a new drug The creation of a new drug can be divided into three main phases: I. Drug discovery: from therapeutic concept to molecule II. Drug development: from molecule to registered product III. Commercialization: from product to therapeutic application to sales Drug Discovery & Development, Overview A drug target can be a receptor/ion channel, enzyme, hormone/factor, DNA, RNA, nuclear receptor, or other, unidentified, biological entity Once drug targets are identified, they are exposed to a large number of compounds in an in vitro or cell-based assay Compounds that elicit a positive response in a particular assay are called “hits.” Hits that continue to show positive response in more complex models rise to “leads” (lead identification) A selected few of the optimized leads (candidate drugs) are then advanced to preclinical testing and clinical testing and therefore passed along to the product development staff Creation of a new drug Before the start of any new project, the creation plan is judged by the following criteria: 1. The drug’s scientific strength and originality 2. Development and marketing issues. For example: i. If the therapeutic target is an ill-defined clinical disorder, e.g., chronic fatigue syndrome, will it be possible to measure clinical efficacy objectively? ii. Does the project face stiff competition from other companies working in the same area, or from drugs already in clinical use? iii. Is it likely that an esoteric drug delivery system will be required, and if so, can this be developed? iv. If the drug is successfully developed, is the expected market sufficient to justify the cost of development? It is essential to keep such issues constantly under review, and to adapt the project plan if necessary Creation of a new drug, contd. As recently as 25–30 years ago in most companies, drug creation was much more compartmentalized: Scientists produced molecules with interesting pharmacological properties Development functions were responsible for checking their safety and turning them into registrable drugs The marketing department generated sales and turned them into revenues At the time, this worked well, and many companies prospered The drop-out rate was not excessive, because regulatory requirements were less stringent The failures rate was not unduly expensive in terms of time and resources lost Creation of a new drug, contd. In the last two decades, biomedical science has advanced dramatically: Drug discovery and development have become more technology-driven and, hence, expensive Regulatory requirements became much more stringent The competition is more intense With bigger teams, and more complex multidisciplinary tasks, effective project management has become much more important than it used to be to keep costs and delays to a minimum The increased amount of work being done in partnership with other companies or with academic groups, adding the need for alliance as well as project management Drug discovery phase of a typical project aimed at producing a new synthetic drug Drug discovery starts with the choice of a disease area and defining the therapeutic need that is to be met It then proceeds to the identification of the biochemical, cellular or pathophysiological mechanism that will be targeted, and, if possible, the identification & validation of a molecular ‘drug target’ The next step is the identification of a lead structure This is followed by the design, testing and fine-tuning of the drug molecule to the point ‘Drug candidate’ where it is deemed suitable for development