Technologies Associated with Pharmaceuticals Drugs

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Technologies Associated with Pharmaceuticals
(Drugs)
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Drugs

• Drug - substance other than food or water that
  affects how body functions
• Medicine or pharmaceutical - drug beneficial to
  human health
• gt25,000 prescription drugs and 300,000
  non-prescription drugs available in US

Suchocki, Chemistry, 2nd, Benjamin, 2004, 452
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Natural Sources of Drugs

• Most common natural sources of drugs are plants,
  animals, and fungi
• 3000 new drugs are discovered annually from
  components of plants
• Only 5000 plants out of estimated 250,000 have
  been studied exhaustively as drug sources
• More than half of all plants exist solely in the
  tropical rain forests that are rapidly being
  destroyed by slash/burn agriculture

Suchocki, Chemistry, 2nd, Benjamin, 2004, 452
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Study of Drugs

• Two major components medicinal chemistry and
  pharmacology
• Medicinal chemistry - the discovery,
  identification, synthesis, development of new
  drugs and optimization of existing drugs
• Pharmacology - study of how chemical substances
  interact with living systems

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Pharmacology

• Pharmacokinetics - what the body does to a drug
  how a drug is absorbed, metabolized, and
  eliminated by body
• Pharmacodynamics - what a drug does to body
  common targets of drugs are substances involved
  in metabolic pathways (enzymes) or substances
  involved in signaling pathways (nervous system or
  endocrine system)

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Pharmacodynamics - Basis for Drug Design
The model used to explain how drugs function is
essentially the same lock/key model that was used
to explain enzymes
Complementary forces (polarities and H-bonding
potentials)
Complementary topographies (sizes and shapes of
portions of surfaces of drug and of receptor
molecules)
Schaumberg, Concerning Chemistry,
Wiley,NY,1974,226 and 229
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Drug Actions Based on Drug/Receptor Model
Drug
Drug can be an agonist (drug which fits and
activates a specific receptor) or antagonist (a
drug that fits and deactivates a specific
receptor by blocking receptor from its natural
substrate)
Staniski et al, Chemistry in Context,4th,McGraw
Hill, IA,2003, 407
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Medicinal Chemistry - discovery of new drugs

• In the past most drugs have been discovered
  either by identifying the active ingredient from
  traditional remedies or by serendipitous
  discovery
• Drug design is the approach of finding drugs
  based on molecular structures size, shapes,
  polarities, and potential for H-bonding.

http//encyclopedia.thefreedictionary.com/drugdis
covery
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Discovery of Drugs from Natural Sources

• Identification of new active compounds (called
  hits) by screening natural materials (plants,
  animals, fungi,etc) for desired biological
  properties
• Optimization - synthetic modification of hits to
  obtain maximum potency and selectivity with
  minimum toxicity
• Development - large scale production and
  formulation needed for clinical trials

http//encyclopedia.thefreedictionary.com/drugdis
covery
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Case Study of a Drug

• In 400 BC, Hippocrates, Father of Medicine, used
  an extract, prepared by boiling bark from a
  willow tree in water, to reduce fevers and pain
• This folk remedy was used for centuries, but was
  not scientifically studied until 1827 when an
  active component, salicin, was isolated

Snyder, Extraordinary Chemistry, Wiley, NY, 1992,
604
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Salicin from willow bark reacts with water to
produce glucose and salicyl alcohol. In the
body, salicyl alcohol is oxidized to salicylic
acid which is the active substance that reduces
fever (antipyretic), pain (analgesic), and
inflammation (anti-inflammatory agent) in humans
Identification
(Metabolic change)
(Metabolite)
Snyder, Extraordinary Chemistry, Wiley, NY, 1992,
605
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Although salicylic acid reduces pain, fever, and
inflammation, it is far too corrosive to tissues
in the stomach to be taken internally by most
people. In 1893 Felix Hofman, a chemist working
for the Bayer firm in Germany, converted
salicyclic acid to acetylsalicylic acid which can
be better tolerated by most people.
Development current sales are about 80 billion
tablets per year in US alone.
Snyder, Extraordinary Chemistry, Wiley, NY, 1992,
606
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Pharmacodynamics of Aspirin
Enzyme in an injured cell catalyzes conversion of
fatty acids into prostaglandins which cause
swelling and pain.
Aspirin reduces pain by deactivating the enzymes
that catalyze the production of prostaglandins -
antagonist
Snyder, Extraordinary Chemistry, Wiley, NY, 1992,
607
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Synthetic Analgesics
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Some 40 drugs with structures related to aspirin
have now been patented including Tylenol and
Advil.
These substances also deactivate enzymes that
convert fatty acids to prostaglandins.
Joesten et al, Chemistry, Saunders, PA, 1988, 392
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Rational Drug Design
Keep removing structural parts of the drug
molecule until the irreducible minimum structure
required for drug activity is determined. A new
drug can then be synthesized containing the
active donor site with other functional groups to
adjust polarities of bonds in active site.
Schwartz et al, Chemistry in Context,Brown,
IA,1994,308
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Process of Drug Testing

• Preclinical trials on animals to establish safety
  
• Then 4 phases of clinical trials on humans
• Phase I - small group (20) of healthy humans
  determine safety pharmacokinetics (how drug is
  absorbed, metabolized, excreted) and
  side-effects
• Phase II - several hundred persons with disease
  randomized/blinded trials using placebos ED50,
  TD50, therapeutic indices determined

http//www.huntington-study-group.org/WHAT20IS20
A20CLINICAL20TRIAL.html
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Clinical Trials

• ED50, effective dose - dose that produces
  therapeutic effect in 50 of test subjects
• TD50, toxic dose - dose that produces specific
  unwanted side-effect in 50 of test subjects
• Therapeutic index TD50/ED50 Large index means
  highly effective with low toxicity (rare)
• Phase III - several thousand persons with
  disease risks/benefits fully assessed if
  approved by FDA goes on market
• Phase IV - monitor for long-term effects
  determine pharmacodynamics of drug (how its acts
  on disease)

Waldron, Chemistry of Everything,Pearson,2007,
518-519
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Receptors Commonly Targeted by Drugs

• Typically a drug target is a key molecule
  involved in a particular signaling pathway or a
  metabolic pathway that is specific to a disease

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Drugs that Inhibit Intercellular Signaling

• The essence of multi-cellularity is the
  coordinated interaction of the various kinds of
  cells that make up the body
• Coordinated interaction requires that cells
  communicate with each other
• Cellular communication involves two types of
  signal carriers chemical or a combination of
  electrical and chemical

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Two Types of Signal Systems

• A. Endocrine system chemical signaling in which
  substances (hormones) are secreted into blood by
  endocrine glands and carried by blood to the
  responding cell
• B. Nervous system combination of chemical and
  electrical signaling in which electrical impulses
  from the brain are transmitted via the central
  nervous system to muscles and glands

http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/S/Synapses.html
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A. Endocrine Signaling Hormones

• Water soluble hormones proteins, peptides,
  modified amino acids, amines
• Lipid soluble hormones steroids
• Hormones are extremely potent
• Can isolate only 5 mg of testosterone (male
  hormone) from 1 ton of bull testes or 12 mg of
  estradiol (female hormone) from 4 tons of pig
  ovaries

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Production Sites for Hormones
http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/E/Endocrines.gif
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Transportof Hormones
Biomolecules are large, but only a small portion
of a biomolecule (receptor) is involved in
signaling
http//www.emc.maricopa.edu/faculty/farabee/BIOBK/
BioBookENDOCR.html
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Mechanism of Signaling by Water Soluble Hormones
Water soluble hormones (proteins) act on surface
receptors and do not enter the cell
http//www.emc.maricopa.edu/faculty/farabee/BIOBK/
BioBookENDOCR.html
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http//www.emc.maricopa.edu/faculty/farabee/BIOBK/
BioBookENDOCR.html
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Mechanism of Signaling by Lipid Soluble Hormones
Lipid soluble hormones (steroids) pass through
the cell membrane, form a receptor-steroid
complex that enters nucleus of cell and activates
a specific gene
http//www.emc.maricopa.edu/faculty/farabee/BIOBK/
BioBookENDOCR.html
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Drugs with Steroid Structure
Helmprecht/Friedman, Basic Chemistry,McGraw
Hill,NY,1977, 365-9
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Steroid Sex Hormones - Lipids
Norethinodrone mimics progesterone and sends a
false message that a pregnancy has been
established thus stopping ovulation
Joesten et al, Chemistry Impact on
Society,Saunders,Phildelphia,1988, 407-408
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Safe Estrogen Mimics - the Pill used since 1960
These two estrogen agonists are the components of
the first birth control pill called Enovid.
Long-term usage has shown them to be relatively
safe.
Hill/Kolb, Chemistry for Changing Times, 8th,
Prentice Hall, NJ, 1998, 554
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Female Hormone
Progesterone activity is essential for
implantation of the embryo in uterine cells,
without this activity, the developing embryo is
spontaneously aborted
Schwartz et al, Chemistry in Context,Brown,
IA,1994,316
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B. Drugs that Inhibit Nervous System Signaling

• Nerves are tissues that carry electric signals to
  and from the brain
• Coordination by the nervous system is both
  electrical and chemical
• Unlike wires, nerves are not continuous but have
  tiny fluid-filled gaps called synapses

http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/S/Synapses.html
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Cont'd

• The transmission of the nerve signal across
  these gaps is by means of small molecules called
  neurotransmitters (usually water soluble peptides
  or amines)
• Distinction between nervous and endocrine
  coordination is nervous co-ordination is faster
  and more localized

http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/S/Synapses.html
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Nervous System Signaling Neurotransmitters
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Neurotransmitter Recognition
Neurotransmitters depend on catalysts for their
formation and degradation. Catalysts recognize
their substrates by complementary sizes, shapes,
polarities, and potential for H-bonding.
Hill/Kolb, Chemistry for Changing Times, 8th,
Prentice Hall, NJ, 1998, 596
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Local Anesthetics - Antagonists - Block
Neurotransmission
Cocaine donor sites
Cocaine
Novocaine
Xylocaine
Snyder, Extraordinary Chemistry, Wiley, NY,1992,
620
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Agonists that Filter Pain Signals at Brain
An Endorphin peptide
Endorphins are present in brain in low
concentrations. Their function is to temporarily
filter out pain signals when under high stress
without interfering with other sensory signals.
Morphine fits same receptors and mimics
endorphins but with an enhanced response
dependent on concentration.
Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997, 23-10-11
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Comparison of Endorphin and Morphine
Morphine
Endorphin
The left ends of both molecules likely serve as
the donor ends and are similar in size, shape,
polarity, and H-bonding.
Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997, 23-10-11
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Modifying Agonist Properties
Structures of drugs can be modified to increase
effective-ness and reduce side effects
Crosses blood-brainbarrier faster thanmorphine
Snyder, Extraordinary Chemistry, Wiley, NY,1992,
611,612,618
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Antimetabolites - Drugs that alter metabolism
Prontosil dye was observed to kill bacteria.
Found that its ability to kill bacteria is due to
formation of sulfanilamide formed when it reacts
with water.
Joesten et al, Chemistry Impact on
Society,Saunders,Phildelphia,1988, 396
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III A. Sulfanilamide Functions as an Antagonist
(PABA)
Antagonist
Joesten et al, Chemistry Impact on
Society,Saunders,Phildelphia,1988, 396
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Normal Synthesis of Folic Acid by Bacteria
Helmprecht/Friedman, Basic Chemistry for the Life
Sciences, McGraw Hill,NY, 1977, 411
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Sulfa Drug Blocks Folic Acid Synthesis in Bacteria
Folic acid is essential to cell wall production
-loss kills bacteria
H
Helmprecht/Friedman, Basic Chemistry for the Life
Sciences, McGraw Hill,NY, 1977, 411
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Structures of drugs can be modified to increase
effectiveness and reduce side effects resulting
from fitting additional receptor sites
Over 5000 derivatives have been made and studied
Hardwick/Knobler, Chemistry Man and Matter,
Ginn, MA,1970, 444
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IIIB. Antimetabolites that Inhibit Uncontrolled
Growth of Part of an Organism (Cancer)
Nitrogen mustards are less toxic nitrogen
derivatives of highly toxic mustard gas
Joesten et al, Chemistry Impact on
Society,Saunders,Phildelphia,1988, 404
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Cyclophosphamide - Current Nitrogen Mustard
Joesten et al, Chemistry Impact on
Society,Saunders,Phildelphia,1988, 404
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How N-Mustards Function
N-mustard covalently links the two strands of DNA
together making it impossible for cell division
to occur since DNA cannot replicate. The covalent
cross-link, -CH2-CH2-N-CH2 -CH2- ,
isrepresented by the black rectangle.
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IIIC. Developmental Drug for Prostate Cancer
What structural features make this a logical
choice? Hint think of N-mustard and of steroidal
hormones.
15 atom-chain
CEN, ACS, 8/22/05, 38
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ChemBiol, Vol 12, 779-787, July, 2005
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Low Success Rate in Drug Development

• 1/50 tested shows promising bio-activity
• 1/100 modifications of these is useful
• 1/10 of these successfully passes clinical trials
  and becomes a market-able drug
• Low success rate (and high legal costs) translate
  to high cost to consumer

Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997, 23-2
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Causes of Low Success Rate

• Drug must have appropriate solubility
  characteristics (fat versus water)
• Drug must be reasonably resistant to chemical
  degradation in the body
• Drug must not interfere with any other aspects of
  biochemistry of the body
• Drug must have a specific structure to be able to
  elicit a specific response

Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997, 23-2
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Structural Complication
Optical Isomers - two different drugs with same
atoms, same bonds, but different spatial
orientations
Levomethorphan is an addictive analgesic
prescription drug, while Dextromethorphan is
non-addictive and can be sold over-the- counter
as a cough suppressant. What is the structural
difference?
Schwartz et al, Chemistry in Context,Brown,
IA,1994,303,410
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Testing for Optical Isomers
View-1
View-2
Superimposable
Two views of the same molecule
Superimposable means that the structures match -
i.e., they have the same kinds of atoms in the
same locations when the structures are placed on
top of each other.
If structures are superimposable, they represent
different views of the same molecule and are not
isomers.
Bettleheim/March, Organic and Biochemistry,2 nd,
Saunders, PA, 1995, 253
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Testing for Optical Isomers
Isomer-I
Isomer-2
Non-superimposable
Two different molecules
Molecules that are non-superimposable mirror
images to each other are two different molecules
and are called optical isomers.
Any molecule containing a chiral carbon atom (one
that has four different groups bonded to it) has
two optical isomers.
Bettleheim/March, Organic and Biochemistry,2 nd,
Saunders, PA, 1995, 251
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Optical Isomers of Ibuprofen
Ibuprofen has a chiral carbon Which carbon atom
is the chiral C-atom?
Only one of the two isomers is physiologically
active.
The same reaction that produces L-ibuprofen also
produces D-ibuprofen so that a 50-50 mixture
(called racemic mixture) is obtained.
Over-the-counter ibuprofen is the racemic
mixture.
Why don't optical isomers have the same
properties?
Schwartz et al, Chemistry in Context,Brown,
IA,1994,303,410
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Drug molecules that exist as optical isomers do
not fit the same receptor site and hence do not
have the same therapeutic properties. One may be
useful while the other may be either harmless
(ibuprofen) or could have other properties such
as annoying or even dangerous side-effects.
Mirror Image
Molecule
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Optical Isomers of Thalidomide
Sedative
Teratogen (birth defects)
http//www.le.ac.uk/chemistry/teach/year1/LECT8_fi
les/image014.gif
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Optical Isomers of Thalidomide
http//colossus.chem.umass.edu/genchem/chem102/Art
icles/Article_Images/thalid3.jpg
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Taxol - drug used in treating breast cancer
Number of optical isomers 2n where n number
of chiral carbon atoms in the molecule. The more
chiral centers in a molecule, the more difficult
it is to manufacture the drug.
Taxol has 1024 optical isomers!
http//adeviq-spin.mega.com.pl/taxolred.gif
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I. Drug Discovery and Development

• There are about 1,850 substances marketed
  worldwide as drugs
• 523 (28) of these have active ingredients that
  come directly from, or are based on, chemicals
  from plants and other natural sources

Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997, 23-2 and Ohio State Quest, Winter
1996, p. 13
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Contd

• Only 10-15 of the 250,000 higher plants
  worldwide have been tested for components for
  possible drug use
• Half of world's flowering plants exist in
  tropical rain forests which are rapidly being
  destroyed by humans
• Medicinal chemists modify natural substances to
  make drugs that are more effective, safer, and
  have less side-effects
• FDA provides approval and oversight

Fox/Whitesell, Organic Chemistry, 2nd, Jones and
Bartlett,1997,23-3 and ChemTech, July 1996, 47
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Pharmacodynamics
Drugs function by binding to some component of a
cell, generically called a receptor
Drug "recognizes" its receptor by virtue of
complement-ary sizes, shapes, bond polarities and
regions capable of H-bonding - structure is
critical
Schaumberg, Concerning Chemistry,
Wiley,NY,1974,226 and 229
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Drug Structures

• Since all molecular recognition depends on
  complementary sizes, shapes, polarities, and
  H-bonding, it is possible to synthesize other
  molecules (drugs) which fit receptor or enzyme
  sites
• Once a drug occupies a receptor site, it can
  either activate or deactivate a natural cellular
  response