Transcript Lecture 01 - Cal State LA

Biol/Chem 444 Drug Discovery and Development
Introduction
Drugs:
Targets:
Natural sources Synthetic sources
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
History of Drug Discovery
•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)
HO O
As
O
H 2N
ClH.H2N
HO
NH2 .HCl
As As
OH
Na+
Atoxyl
Salvarsan
•1960 - First successful attempt to relate chemical structure to
biological action quantitatively (QSAR = Quantitative structureactivity relationships). Hansch and Fujita
History of Drug Discovery
•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
O
H 2N
O
OCH2CH2N(C2H5 )2
Procaine
H 2N
NHCH2CH 2N(C 2H5) 2
Procainamide
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.
Profile of Today’s Pharmaceutical Business
•Problems, continued:
•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.
Profile of Today’s Pharmaceutical Business
•Interdisciplinary!!!
Profile of Today’s Pharmaceutical Business
•Combination of large pharma and small biotech (outsourcing,
licensing new technologies, “alliances”)
•Mergers, etc:
Profile of Today’s Pharmaceutical Business
•Global economy
China: new focus by industry
Profile of Today’s Pharmaceutical Business
•“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
Profile of Today’s Pharmaceutical Business
•“Filling the Pipeline”… Small molecules vs. Biologics
2004
2006
Profile of Today’s Pharmaceutical Business
•“Filling the Pipeline”… Small molecules vs. Biologics over time
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.
Profile of Today’s Pharmaceutical Business
•“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.
Profile of Today’s Pharmaceutical Business
•“Filling the Pipeline”… Top companies and Approved Drugs
Profile of Today’s Pharmaceutical Business
•Types of targets
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).
Profile of Today’s Pharmaceutical Business
•Rising costs of one drug: 1999 $600million. Today $897million.
Clinical development costs 3/5 that amount.
Profile of Today’s Pharmaceutical Business
•In 2004, industry spent
twice as much on R&D as it
did for promotion of the drug
Profile of Today’s Pharmaceutical Business
•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
Profile of Today’s Pharmaceutical Business
•Patents (continued)
•In 2006, 6 major products lost patent protections
•Companies attempting to retain profits by
reformulating. (Ambien CR = controlled release)
Profile of Today’s Pharmaceutical Business
•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)
Profile of Today’s Pharmaceutical Business
Figure 2 | Mean clinical and approval phase lengths for smallmolecule drugs approved in the United States during 1970–2001.
Profile of Today’s Pharmaceutical Business
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.
Profile of Today’s Pharmaceutical Business
•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?
•Consumer approval of the industry
has declined (79% approval in
1997; 44% approval in 2004)
Focus on diseases of rich Americans
Pursue "blockbuster drugs" (not
antimicrobials, etc)
Mergers; rely on biotech companies for
innovations
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.
(Note: Molecular Conceptor software uses locks (biological targets) and
keys (drugs) to illustrate the concepts involved in drug discovery)
•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
Drug Discovery overview
Approaches to lead discovery:
•Serendipity (luck)
•Screening
•Chemical Modification
•Rational
Drug Discovery overview
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
Drug Discovery overview
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.
Drug Discovery overview
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.
Drug Discovery overview
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.
Drug Discovery overview
4. Rational Drug Design - Cimetadine (Tagamet) - continued
a. Chemical modifications were
made of the lead = LEAD
OPTIMIZATION:
c. Replacement of the group led to
an effective and well-tolerated
product:
b. More potent and orally active,
but thiourea found to be toxic in
clinical trials
d. Eventually replaced by Zantac
with an improved safety profile
Drug Discovery overview
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.
Drug Discovery overview
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 overview
Rational 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 overview
Rational 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 overview
Rational Drug Design - Receptor-based Drug Design
•Examine the 3D structure of the biological target (usually an Xray 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 overview
Rational 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 overview
Rational Drug Design
Typical projects are not purely receptor-based or
pharmacophore-based; they use combination of information,
hopefully synergistically
Drug Discovery overview
Rational 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 overview
Rational 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 pharmacophorebased projects.
Drug Discovery overview
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. 13-17
Chemical and Engineering News 2007, 85 (49) p. 13-24
Chemical and Engineering News 2006, 84 (49)
Chemical and Engineering News 2006, 84 (44) p. 14-20
Chemical 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