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Technologies Associated with Pharmaceuticals (Drugs). Drugs. Drug - substance, other than food or water, that affects how a body functions Medicine or pharmaceutical - drug beneficial to human health >25,000 prescription drugs and 300,000 non-prescription drugs available in US.

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Drugs l.jpg
Drugs

  • Drug - substance, other than food or water, that affects how a body functions

  • Medicine or pharmaceutical - drug beneficial to human health

  • >25,000 prescription drugs and 300,000 non-prescription drugs available in US

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


Medicinal chemistry l.jpg

Medicinal Chemistry

Drug Discovery

Drug Testing

Case Study


Medicinal chemistry discovery of new drugs l.jpg
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

  • Rational drug design is the approach of synthesizing drugs based on similarities in molecular structures.

http://encyclopedia.thefreedictionary.com/drug+discovery


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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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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/drug+discovery


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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/WHAT%20IS%20A%20CLINICAL%20TRIAL.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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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.

Optimization

Development: current sales are about 80 billion tablets per year in US alone.

Snyder, Extraordinary Chemistry, Wiley, NY, 1992, 606


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Pharmacology 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.

Pharmacodynamics

Rational Drug Design

Analgesics


Pharmacology14 l.jpg
Pharmacology 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.

  • 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 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.

(Substrate)

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 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.

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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Pharmacodynamics of Aspirin 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.

*

**

Arachidonic acid

*Prostaglandins are biochemicals that initiate a pain signal, inflammation, and fever.

**Analgesic - a drug that enhances the ability to tolerate pain without abolishing nerve sensations. Aspirin is an antagonist - it fits and blocks the enzyme site, thus decreasing prostaglandin production.

Suchocki, Chemistry, 2nd, Benjamin, 2004, 485


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Rational Drug Design of Other Analgesics 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.

Drug design is based on QSAR - quantitative structure activity relationships. Drugs that have the same key donor groups in the same relative locations in their structures likely form the same drug/receptor complex and will exhibit similar activities.

Analgesics have a benzene ring and C=O separated by one atom

Aspirin*

Ibuprofen*(Advil, Motrin)

Naproxen*(Aleve)

Acetaminophen(Tylenol, Datril)

*NSAID = non-steroidal anti-inflammatory drug

Suchocki, Chemistry, 2nd, Benjamin, 2004, 486


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Steroidal Anti-inflammatory Drugs 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.

Anti-inflammatory Steroids

Hydrocortisoneagonist

Cortisoneagonist

Helmprecht/Friedman, Basic Chemistry,McGraw Hill,NY,1977, 365-9


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Analgesics that Filter Pain Signals at Brain 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.

An Endorphin peptide

3

2

1

3

2

1

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.

QSAR: both endorphin and morphine have benzene ring and N separated by 3 C atoms. Morphine functions as an agonist.

Fox/Whitesell, Organic Chemistry, 2nd, Jones and Bartlett,1997, 23-10-11


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Rational Drug Design 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.

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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Rational Drug Design 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.

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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Other Drug Targets 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.

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

  • Signaling pathways involve two types of signal carriers: chemical or a combination of electrical and chemical


Signal pathways l.jpg
Signal Pathways 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.

  • 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 to and from the brain are transmitted via the central nervous system

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/Synapses.html


A drugs that inhibit nervous system signaling l.jpg
A. Drugs that Inhibit Nervous System Signaling 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.

  • Nerves are tissues that carry electric signals to and from the brain

  • Unlike wires, nerves are not continuous but have tiny fluid-filled gaps called synapses

  • The transmission of the nerve signal across these gaps is by means of small molecules called neurotransmitters (usually water soluble peptides or amines)

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/Synapses.html


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Nervous System Signaling: Neurotransmitters 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.

acetylase

Hill/Kolb, Chemistry for Changing Times, 8th, Prentice Hall, NJ, 1998, 596


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Neurotransmitters and Catalysts 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.

Neurotransmitters depend on catalysts for their formation and degradation. Catalyst can be blocked by an antagonist drug. Drugs that block neurotransmission are called anesthetics.

Hill/Kolb, Chemistry for Changing Times, 8th, Prentice Hall, NJ, 1998, 596


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Rational Drug Design 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.

QSAR: acetylcholine has carbonyl and substituted amine functional groups separated by several atoms. Molecules having similar structures can block catalysis needed for neurotransmission (antagonists)

Cocaine

Novocaine

Xylocaine

Snyder, Extraordinary Chemistry, Wiley, NY,1992, 620


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Analgesics, Anesthetics, and Pain Relief 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.

Suchocki, Chemistry, 2nd, Benjamin, 2004, 483


B endocrine signaling hormones l.jpg
B. Endocrine Signaling: Hormones 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.

  • 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 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.

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/E/Endocrines.gif


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Transportof Hormones 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.

Receptors

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 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.

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.htmlhttp://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookENDOCR.html


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Mechanism of Signaling by Lipid Soluble Hormoneshttp://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookENDOCR.html

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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Steroid Sex Hormones - Lipidshttp://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookENDOCR.html

Female Hormone

Male Hormone

Agonist

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 1960http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookENDOCR.html

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 Hormonehttp://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookENDOCR.html

Abortion Pill

Large extra ring makes RU-486 an antagonist for progesterone, i.e., occupies and blocks the progesterone receptor site, but causes no biological activity

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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Drugs that Inhibit Metabolic Pathways (Anti-metabolites)

Folic acid is required to maintain strength of cell walls. Bacteria synthesize folic acid enzymatically using PABA.

Humans obtain folic acid from food and do not synthesize it. The bacterial enzyme can be blocked by a drug of proper design.

Suchocki, Chemistry, 2nd, Benjamin, 2004, 458


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Rational Drug Design (Anti-metabolites)

Sulfanilamide - antimetabolite that was the first antibiotic

Suchocki, Chemistry, 2nd, Benjamin, 2004, 459


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Rational Drug Design (Anti-metabolites)

Replace one H of NH2 group

Substituting R groups for H on amine group changes polarities and hence strength of forces binding drug/receptor complex. Over 5000 derivatives were made and studied.

Hardwick/Knobler, Chemistry: Man and Matter, Ginn, MA,1970, 444


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Nitrogen Mustard - antimetabolites that was the first drug used in cancer chemotherapy

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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Pharmacodynamics used in cancer chemotherapy

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. Functions as an antimetabolite which interferes with replication.


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Rational Drug Design used in cancer chemotherapy

Current chemotherapy uses cyclophosphamide, which reduces nausea.

Joesten et al, Chemistry: Impact on Society,Saunders,Phildelphia,1988, 404


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Rational Drug Design - drug designed for prostate cancer - currently in pre-clinical trials

N-mustard

Steroid

15 atom-chain

C&EN, ACS, 8/22/05, 38


Slide46 l.jpg

Proposed Pharmacodynamics currently in pre-clinical trials

Chem&Biol, Vol 12, 779-787, July, 2005


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Low Success Rate in Drug Development currently in pre-clinical trials

  • 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 currently in pre-clinical trials

  • 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 currently in pre-clinical trials

Mirror

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 currently in pre-clinical trials

View-1

View-2

Two views of the same molecule

Superimposable

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 currently in pre-clinical trials

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 currently in pre-clinical trials

Chiral atom

(Inactive)

(Analgesic)

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.

Receptor-1

Receptor-1

Mirror Image

Molecule


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Chiral atom 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.

Chiral atom

Optical Isomers of Thalidomide

Sedative

Teratogen (birth defects)

http://www.le.ac.uk/chemistry/teach/year1/LECT8_files/image014.gif


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Optical Isomers of Thalidomide 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.

http://colossus.chem.umass.edu/genchem/chem102/Articles/Article_Images/thalid3.jpg


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Taxol - drug used in treating breast cancer 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.

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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