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The Organic Chemistry of
Drug Design and Drug Action
Chapter 1
Introduction
Drug Discovery
One way to “discover” drugs
Figure 1.1
Medicinal Chemistry
The 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) and toxicology
Medicinal Chemistry Folklore
Earliest medicines ~ 5100 years ago
Chinese emperor Shen Nung - book of herbs, Pen Ts’ao
Ma Huang
Used as a heart stimulant and for nasal and chest congestion.
Contains ephedrine
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 digitalis
Drugs from traditional sources
Quinine came from South
America
Digitalis came from foxglove in
Britain
Discovery of New Drugs
Nature is still an excellent source of new drugs
(or precursors of new drugs).
Almost 40% of new drugs approved in the last
20 years are natural products or derived from
natural products.
60% of antitumor and anti-infective drugs are
natural products or derived from natural
products.
Drug Discovery Without a Lead
Penicillins
1928 - Fleming
Bacteria lysed by green mold; could not reproduce effect serendipity.
• mold spore contaminates culture dish
• left dish on bench top while on vacation
• weather was unseasonably cold
• particular strain of mold was a good penicillin producer
Could not get penicillin in a useful clinical form
1940 - Florey (Oxford)
Succeeded in producing penicillin in a useful clinical form.
Discovery was not published until late 1940’s after World
War II so Germans would not benefit from it.
Structure of penicillin elucidated in 1944 - X-ray
crystal structure by Dorothy Hodgkin (Oxford)
Sulfa antibiotics were discovered
in 1935
Serendipitous Discovery of Librium without a Lead
In 1955 Roche set out to prepare a series of
benzheptoxdiazines (1.14) as potential new tranquilizer
drugs, but the actual structure was found to be that of a
quinazoline 3-oxide (1.15).
No active compounds were found, so the project was abandoned
In 1957, during a lab cleanup, a vial containing what was thought to be
1.16 was sent for testing, and it was highly active.
Further analysis showed that the actual structure of the compound was
the benzodiazepine 4-oxide, 1.13, presumably produced in an
unexpected reaction of the corresponding chloromethyl quinazoline
3-oxide (1.16) with methylamine.
Scheme 1.1
Librium
Valium is a more active analogue of
Librium
Drugs from Drug Metabolism Studies
The nonsedating antihistamine terfenadine
(Seldane) caused abnormal heart arrhythmias
in some patients (binds to hERG*), so it was
withdrawn from medical use.
*human Ether-a-go-go Related Gene
Fexofenadine (Allegra), a metabolite of
terfenadine, also is a nonsedating
antihistamine that does not cause heart
arrhythmias, so it replaced terfenadine
Sulindac is metabolized to the
active compound (prodrug)
Drug Discovery from Clinical
Observations
Viagra (sildenafil citrate) tested as antihypertensive/
antianginal drug.
Phase II trials not great, so went back to Phase I
(healthy volunteers) at a higher dose.
Very happy volunteers .
Reported prolongation of penile erections
Mechanism of Action of Viagra
L-Arg
NO
synthase
Nitric oxide
Erection
stimulates
Guanylate cyclase
GTP
cGMP
smooth
smooth
muscle
muscle
constriction
relaxation
GMP
PDE 5
Phosphodiesterase
isozyme in corpus
cavernosum (in penis)
increased
decreased
blood
blood
flow
flow
Mechanism of Action of Viagra
L-Arg
NO
synthase
Nitric oxide
Erection
stimulates
Guanylate cyclase
GTP
cGMP
smooth
smooth
muscle
muscle
constriction
relaxation
GMP
PDE 5
Viagra blocks
this enzyme
Phosphodiesterase
isozyme in corpus
cavernosum (in penis)
increased
decreased
blood
blood
flow
flow
Dramamine and Zyban also were found
from side effects in clinical trials
Rational Drug Discovery
Drugs generally are not discovered directly; first a lead
compound is identified.
Lead compound
Prototype having desired activity but also other
undesirable characteristics, e.g., toxicity, other
activities, insolubility, metabolism problems, oral
bioavailability
Lead modified by synthesis
• to amplify desired activity
• to minimize or eliminate undesirable properties
Produces a drug candidate (compound worthy of
extensive biological, pharmacological, and animal
testing)
Drug Discovery
Average time to bring a drug to market is 12-15
years.
For every 20,000 compounds evaluated in animals,
10 make it to human clinical trials, of which 1 goes
to market.
Lead Discovery
First a bioassay (or screen) is needed
Means to determine in vitro or in vivo,
relative to a control, whether the
compound has the desired activity* and
relative potency**.
* particular pharmacological effect (e.g., antibacterial
effect)
** strength of the effect
Lead Discovery Approaches
1. Random screening - only approach before 1935; screen
every compound you have; still a useful approach;
streptomycin and tetracyclines identified in this way
2. Nonrandom (or Targeted or Focused) screening - only
screen compounds related to active compounds
3. Drug metabolism studies - metabolites produced are
screened for the same or other activities
4. Clinical observations - new activities found in clinical
trials; Dramamine tested as antihistamine (allergy) - found
to relieve motion sickness; Viagra tested as
antihypertensive - found to treat erectile dysfunction
Lead Discovery Approaches (cont’d)
5. Rational approaches - identify causes for
disease states:
• imbalance of chemicals in the body
• invasion of foreign organisms
• aberrant cell growth
Identify biological systems involved in disease
states; use natural receptor ligand or enzyme
substrate as the lead; a known drug also can be
used as a lead
Rational Drug Design
Identify Target
Chemical imbalances - antagonism or agonism
of a receptor; enzyme inhibition
Foreign organism and aberrant cell growth enzyme inhibition; DNA interaction
Protein drug targets
Examples of drug targetdopamine D3 receptor
FIGURE 1.4 Small molecule drug (quinpirol) bound to its protein target (dopamine D3 receptor). The cartoon on the
right shows how a protein, such as the D3 receptor, spans the membrane of a cell. The D3 receptor in red depicts its
conformation when the drug is bound. The D3 receptor in yellow depicts its conformation when no drug is bound.
“TM” designates a transmembrane domain of the protein. Note the significant differences between the red and yellow
regions on the intracellular side of the membrane, prompted by the binding of quinpirol from the extracellular side
(Ligia Westrich, et al. Biochem. Pharmacol. 2010, 79, 897–907.) On the right is a molecular representation of the fluid
mosaic model of a biomembrane structure. From Singer, S. J.; Nicolson, G L. Science. 1972, 175, 720. Reprinted
with permission from AAAS.
Example of drug target-DNA
FIGURE 1.5 Small molecule drug (daunomycin) bound to its nucleic acid target (DNA). The different colors represent
C (yellow), G (green), A (red), and T (blue). Mukherjee, A.; Lavery, R.; Bagchi, B.; Hynes, J. T. On the molecular
mechanism of drug intercalation into DNA: A computer simulation study of the intercalation pathway, free energy, and
DNA structural changes. J. Am. Chem Soc. 2008, 130, 9747. Reprinted with permission from Dr. Biman Bagchi, Indian
Institute of Science, Bangalore, India. Journal of the American Chemical Society by American Chemical Society.
Reproduced with permission of American Chemical Society in the format republish in a book via Copyright Clearance
Center.
Example of drug target-enzyme
FIGURE 1.6 Interaction of the drug zanamivir with its enzyme target
neuraminidase. (a) Model derived from an X-ray crystal structure; zanamivir is
depicted as a space-filling model at center: carbon (white), oxygen (red), nitrogen
(blue), and hydrogen (not shown). Only the regions of the enzyme that are close
to the inhibitor are shown: small ball and stick models show key enzyme side
chains (b) Schematic two-dimensional representation showing noncovalent
interactions (dotted-lines) between zanamivir and the enzyme.
The biosynthesis of cholesterol is
a target for statin drugs
Acetylcholinesterase is a target
for Alzheimer’s drugs
Problems with Targeted Approaches
• Cannot predict toxicity/side
effects.
• Cannot predict
transport/distribution.
• Cannot predict metabolic fate.
• Target in vivo may not be the
desired one.
Drugs with unexpected targets
•
•
Ezetimibe--designed to inhibit cholesterol esterase,
but inhibits cholesterol transport
Pregabalin—designed to activate Glu
decarboxylase, but blocks Ca2+ channels
Alternatives to targets for lead
discovery
•
•
•
Natural substrate or ligand—modify the
structure to obtain desired property.
Natural product—can be adapted to bind
to enzyme or receptor
Screening—screen large number of
compounds to find those that have the
desired property
Drug based on a natural ligand
Drug based on natural products
High-throughput Screens (HTS)
Very rapid, sensitive in vitro screens
Carried out robotically in 1536- or 3456-well titer
plates on sub-microgram amounts of compound
Can assay 100,000 compounds a day
1990 ~ 200,000 compounds screened per year
1995 ~ 5-6  106 compounds screened per year
2000 > 50  106 compounds screened per year
in a large pharmaceutical company
Increase in number of hits (compounds that elicit a
predetermined level of activity)
So far, no increase in rate of the number of drugs
coming on the market.
Other Screening Approaches
Possible to screen compounds for inhibition of an entire
metabolic pathway:
• Combine all enzymes in the pathway (e.g., bacterial cell wall
biosynthesis), add compound, look for accumulation of an
intermediate in the pathway (inhibition of the enzyme that
acted on the intermediate).
Screening also done by electrospray ionization mass
spectrometry.
• Can add large number of compounds (as long as they have
different molecular masses) and look for formation of
noncovalent drug-receptor complexes in the mass spectrum.
The affinity of the ligand (a small molecule that binds to a
receptor) is measured by increasing the collision energy of the
spectrometer.
Lead Modification
Pharmacodynamics Potency of drug binding
to the target.
Pharmacokinetics ADME - Absorption,
Distribution, Metabolism, Excretion; depends
on water solubility and lipid solubility
Toxicity Often due to binding of the drug to
unwanted off-targets—e.g., other enzymes or
receptors.
Toxicity from off-target effects
Clinical Trials
Phase I (3-18 months) - evaluates safety, tolerability,
pharmacokinetics, and pharmacological effects in 20100 healthy volunteers
Phase II (1-3 years) - assesses effectiveness, determines
side effects and other safety aspects, clarifies dosing in
a few hundred patients
Phase III (2-6 years) - establishes efficacy and adverse
effects from long-term use with several thousand
patients
New Drug Application (NDA) submitted to FDA (4-36
months)
Phase IV - results after drug is on market
Epilogue
• For every 20,000 compounds tested in animals, 10 go to
clinical trials, and 1 goes to market
• 12-15 years of research (constant since 1980)
• Cost to get to market
1962 - $4 million
1996 - $350 million
2002 - $600-$800 million
2013 - $1.2-1.8 billion
• Only ~6000 known drugs of the estimated 1060 possible
compounds
Epilogue (cont’d)
• Only ~400-500 different human targets known (< 1% of
human proteome) - may be 5,000-10,000 potential drug
targets
• Genomics (identification of new gene targets) and
proteomics (identification of proteins expressed) are new
directions for drug discovery
• In 2002, for the first time in U.S., generic drug sales were
greater than nongeneric drug sales
• In 2002, only 16 new drugs entered the market (usually 20s
or 30s)
•In 2013, 27 new drugs were approved
Number of New Drugs Declines as R&D Spending Increases
53
21
16
Year
‘04 ‘05 ‘06 ‘07 ‘08 ‘09 ‘10 ‘11
New Drugs 36 20 22 17 24 25 21 35
‘12 ‘13 ‘14
39 27 41
Taken from the Wall Street Journal, February 24, 2004