Biol/Chem 444 Drug Discovery and Development Drugs: Natural sources Synthetic sources Targets: Introduction McCurdy 3/20/08.

Biol/Chem 444 Drug Discovery and Development

Drugs:

Natural sources Synthetic sources

Targets:

Introduction

McCurdy 3/20/08

History of Drug Discovery

•Folk medicine - natural product remedies•Early 19th century - extraction of compounds from plants (morphine, cocaine). Apothecaries (Hoffman-La Roche)

•Late 19th century - fewer natural products used, more synthetic substances. Dye and chemical companies start research labs and discover medical applications. (Bayer) •Industry devoted solely to pharmaceuticals begins•1905 - John Langley: theory of receptive substances


•1909 - First rational drug design. Goal: safer syphilis treatment than Atoxyl (below). Paul Erhlich and Sacachiro Hata wanted to maximize toxicity to pathogen and minimize toxicity to human (therapeutic index). Synthetic: 600 compounds; evaluated ratio of minimum curative dose and maximum tolerated dose. They found Salvarsan (which was replaced by penicillin in the 1940’s)

•1960 - First successful attempt to relate chemical structure to biological action quantitatively (QSAR = Quantitative structure-activity relationships). Hansch and Fujita

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•Mid to late 20th century - understand disease states, biological structures, processes, drug transport, distribution, metabolism. Medicinal chemists use this knowledge to modify chemical structure to ifluence a drug’s activity, stability, etc.•Example: procaine = local anaesthetic; Procainamide = antirhythmic

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Profile of Today’s Pharmaceutical Business

•Drug: Chemical substance that is used to prevent or cure diseases in humans, animals, or plants•Activity: Pharmacological effect on the subject•Potency: quantitative measure of the effect of the drug•Classification schemes - several: chemical structure, pharmacological action, physiological classification•Benefits:

•Improve quality of life and life expectancy (47 years in 1850; 78 years today). Result = shift of population demographics to a more healthy elderly population

•Problems: •Cost, overdose, side effects (COX-2 inhibitors - Vioxx). • Overuse can result in tolerance in humans and resistance in pathogens.


•Found in the environment! •Pharmaceuticals are a small fraction of the thousands of man-made chemicals in the environment.•Feminized male fish… Found in earthworms•Very few found in drinking water (ibuprofen) or sources of drinking water. Way below levels that would affect humans.

•Problems, continued:


•Interdisciplinary!!!


•Combination of large pharma and small biotech (outsourcing, licensing new technologies, “alliances”)

•Mergers, etc:


•Global economy

China: new focus by industry


•“Filling the Pipeline”…using new technologies: Combinatorial synthesis, genomics, “personalized medicine” are promising but expensive. Making more compounds does not necessarily mean finding more drugs; genomic-proteomic output has not had much commercial success - target validation takes a long time.

•Failure rate: 1 in 5000 drugs reach clinical trials; 1 in 10,000 reaches marketing


•“Filling the Pipeline”… Small molecules vs. Biologics

20062004

Number of small-molecule drugs, recombinant proteins and monoclonal antibody therapeutics approved in the United States during 1980–2001. *Total number of each product type approved during 1980–2001. mAb, monoclonal antibody; rDNA, recombinant protein; SMD, small-molecule drug.


•“Filling the Pipeline”… Small molecules vs. Biologics over time


•“Filling the Pipeline”… Top products

Industry has been primarily based on the “blockbuster” model (>$1 billion in sales; high numbers of patients). May not be able to keep coming up with these blockbusters, so they are also focusing on specialty markets and personalized medicine.


•“Filling the Pipeline”… Top companies and Approved Drugs

Figure 1 | Therapeutic target classes. All current therapeutic targets can be subdivided into seven main classes, wherein enzymes and receptors represent the largest part. Adapted with permission from Ref. 1 © American Association for the Advancement of Science (2000).


•Types of targets

•Rising costs of one drug: 1999 $600million. Today $897million. Clinical development costs 3/5 that amount.



•In 2004, industry spent twice as much on R&D as it did for promotion of the drug


•Patents - Patents forbid competitors to use the originators’ inventions.

•They benefit the public by disclosing valuable inventions that might otherwise remain trade secrets•They compensate pharmaceutical companies for risky research projects to discover new drugs.•In 1980’s 5-7 years elapsed before a competing drug appeared; in 1990’s 3 years


•Patents (continued)•In 2006, 6 major products lost patent protections•Companies attempting to retain profits by reformulating. (Ambien CR = controlled release)


•Time to market: 10-12 years. By contrast, a chemist develops a new adhesive in 3 months! Why? (Biochemical, animal, human trials; scaleup; approvals from FDA, EPA, OSHA)

Figure 2 | Mean clinical and approval phase lengths for small-molecule drugs approved in the United States during 1970–2001.



Overall, higher safety concerns (sparked by Vioxx recall in 2004) have made FDA more conservative in approvals, more vocal in warnings, and have made companies more likely to spend more time testing, and to suspend research before clinical trials.


•Economic, social, and political issues - Unlike US, other nations have not raised prices on drugs. Richer nations are subsidizing poorer nations (anti-HIV drugs, for example). How do companies make up for increased costs but no price increases?

Focus on diseases of rich Americans

Pursue "blockbuster drugs" (not antimicrobials, etc)

Mergers; rely on biotech companies for innovations

•Consumer approval of the industry has declined (79% approval in 1997; 44% approval in 2004)

Drug Discovery overview

A drug discovery effort addresses a biological target that has been shown to play a role in the development of the disease or starts from a molecule with interesting biological activities.

•Lead discovery. Identification of a compound that triggers specific biological actions. •Lead optimization. Properties of the lead are tested with biological assays; new molecules are designed and synthesized to obtain the desired properties

(Note: Molecular Conceptor software uses locks (biological targets) and keys (drugs) to illustrate the concepts involved in drug discovery)


Approaches to lead discovery:

•Serendipity (luck)

•Screening

•Chemical Modification

•Rational


1. Serendipity “Chance favors the prepared mind”

1928 Fleming studied Staph, but contamination of plates with airborne mold. Noticed bacteria were lysed in the area of mold. A mold product inhibited the growth of bacteria: the antibiotic penicillin


2. Screening

Testing a random and large number of different molecules for biological activity reveals leads. Innovations have led to the automation of synthesis (combinatorial synthesis) and testing (high-throughput screening).

Example: Prontosil is derived from a dye that exhibited antibacterial properties.


3. Chemical Modification

Traditional method. An analog of a known, active compound is synthesized with a minor modification, that will lead to improved biological activity.

Advantage and Limitation: you end up with something very similar to what you start with.


4. Rational Drug Design; Example - Cimetadine (Tagamet)

Starts with a validated biological target and ends up with a drug that optimally interacts with the target and triggers the desired biological action.

Problem: histamine triggers release of stomach acid. Want a histamine antagonist to prevent stomach acid release by histamine = VALIDATED BIOLOGICAL TARGET.

Histamine analogs were synthesized with systematically varied structures (chemical modification), and SCREENED. N-guanyl-histamine showed some antagonist properties = LEAD compound.


4. Rational Drug Design - Cimetadine (Tagamet) - continued

b. More potent and orally active, but thiourea found to be toxic in clinical trials

c. Replacement of the group led to an effective and well-tolerated product:

a. Chemical modifications were made of the lead = LEAD OPTIMIZATION:

d. Eventually replaced by Zantac with an improved safety profile


4. Rational Drug Design -

Establishes structural relationships between the biological properties and the molecular structures.

Basis of drug-target interactions is molecular recognition: the specific attractions between the chemical groups of a biological target (large protein, usually) and a drug (small molecule, usually).

New molecules that can optimally interact with a biological target can be designed to block or trigger a specific biological activity.


4. Rational Drug Design -

Begins with the design of compounds that conform to specific requirements. The molecules are synthesized, tested. Then the molecule is redesigned, synthesized, tested….

Where do these specific requirements come from? Two sources.1. 3D structure of biological target (receptor-based drug design)2. Structure(s) of known active small molecules

(pharmacophore-based drug design)

Drug Discovery overviewRational Drug Design - Pharmacophore-based Drug Design

•Examine features of inactive small molecules (ligands) and the features of active small molecules (ligands). •Generate a hypothesis about what chemical groups on the ligand are necessary for biological function; what chemical groups suppress biological function.•Generate new ligands which have the same necessary chemical groups in the same 3D locations. (“Mimic” the active groups)

Advantage: Don’t need to know the biological target structure

Drug Discovery overviewRational Drug Design - Typical Pharmacophore-based Project

•The structures of a series of biologically active molecules are known. The goal is to create a novel (patent-able!) structure with improved properties.

•The common structural features to all active molecules are collected in the “pharmacophophore.” •A molecule is designed to mimic the pharmacophore.

Drug Discovery overviewRational Drug Design - Receptor-based Drug Design

•Examine the 3D structure of the biological target (usually an X-ray structure; hopefully one where the target is complexed with a small molecule ligand; if no data is available, look for homologous protein structures/sequences.)•Look for specific chemical groups that could be part of an attractive interaction between the target protein and the drug.•Design a drug candidate that will have multiple sites of complementary interactions with the biological target.

Advantage: Visualization allows direct design of molecules

Drug Discovery overviewRational Drug Design - Typical Receptor-based Project

•The structure of a cancer-related protein complexed with a nonselective inhibitor ligand is known. This is a starting point to design a more selective inhibitor.

•A molecule can be designed that has optimal (more) interactions with the target protein than the original inhibitor.

Drug Discovery overviewRational Drug Design

Typical projects are not purely receptor-based or pharmacophore-based; they use combination of information, hopefully synergistically

Drug Discovery overviewRational Drug Design

•Can pursue both receptor and pharmacophore-based approaches independently•If the binding mode of the ligand and target is known, information from each approach can be used to help the other

Ideally, identify a structural model that explains the biological activities of the known small molecules on the basis of their interactions with the 3D structure of the target protein.

Drug Discovery overviewRational Drug Design - a historical perspective

•1970’s: no biological target structures known, so all pharmacophore-based approaches.

•1990’s: recombinant DNA, cloning, etc. helped the generation of 3D structural data of biological targets.

•Present: plenty of structural data of biological targets, but also improved technology to increase pharmacophore-based projects.


References:Friary, R. Jobs in the Drug Industry A Career Guide for Chemists; Academic Press: San Diego, CA, 2000.Thomas, G. Medicinal Chemistry An Introduction; John Wiley & Sons: New York, NY, 2000.Williams, D. A.; Lemke, T.L. Foye's Principles of Medicinal Chemistry; Lippincott Williams & Wilkins: Baltimore, MD, 2002.Science 2004, 303, 1795-1822.Chemical and Engineering News 2008, 86 (8) p. 13-17Chemical and Engineering News 2007, 85 (49) p. 13-24Chemical and Engineering News 2006, 84 (49)Chemical and Engineering News 2006, 84 (44) p. 14-20Chemical and Engineering News 2006, 84 (25) Special Issue on Pharma.Chemical and Engineering News 2006, 84 (10), 21-27.Chemical and Engineering News 2005, 83 (49), 15-32.Chemical and Engineering News 2005, 83 (23), 21-29.Chemical and Engineering News 2004, 82 (30), 23-32.Chemical and Engineering News 2004, 82 (12), 51-56.Chemical and Engineering News 2004, 82 (49), 18-29.Chemical and Engineering News 2004, 82 (7), 23-36.Molecular Conceptor K3; C1

Biol/Chem 444 Drug Discovery and Development Drugs: Natural sources Synthetic sources Targets: Introduction McCurdy 3/20/08.

Documents

industry slide

antirhythmic slide

fujita slide

drug transport

chemical structure

history of drug discovery

drug classification

rational drug design