Pharmaceutical DrugsPharmaceutical Drugs
Transcript of Pharmaceutical DrugsPharmaceutical Drugs
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Pharmaceutical DrugsPharmaceutical Drugs
Chemistry 199LPharmaceutical Drugs
(Chapter 19)
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Pain relievers and fever reducer: aspirin
(S bl k) (Aspirin)1893Few
(Sunblock)1827
Stomach distress& bleeding
• Analgesic (pain reliever)Antipyritic (fever reducer)
side-effect& bleeding
• Antipyritic (fever reducer)• Anti-inflammatory• Anticoagulent: heart attack and stroke preventionAnticoagulent: heart attack and stroke prevention
Inhibits production of prostaglandins (pain messengers)
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Limitation of Aspirin
(A i i )
• Still causes some intestinal bleeding
(Aspirin)
(not recommended by people facing surgery, child birth, etc.)
• not effective for severe pain, e.g., migraine headachel d l d i i l di d• prolonged use can lead gastrointestinal disorders
• overdose• allergic reactions• allergic reactions• Reye’s syndrome for children with flu or chickenpox
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Aspirin substitutes(Overuse can lead to
Now banned Tylenol
(Overuse can lead to liver/kidney damage)
Advil Aleve Orudis KT
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Cold remedies: Antihistamines
When allergens bind to surface of certain cells, they trigger release of histamine,y ggwhich causes redness, swelling and itching
Antihitamine blocks releases of histaminebut some also enter the brains and act on cellsbut some also enter the brains and act on cells controlling sleep, causing drowsiness.
Other cold remedies: Cough suppressants and decongestantsAll treat only symptoms, not the causeEffect of vitamin C has been observed; reason still unknown
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Infectious diseases
19001995
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Antibacterial drugs: sulfa drugsAntibacterial drugs: sulfa drugs
(Mimic PABA)
(PABA)
Discovered in 1935 by Gerhard Domagk (German chemist)
Needed by bacteria to make folic acid(PABA)
Chemical mimic-type poison for bacteriay g ( )
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An antibiotic: penicillin
A colony of Penicillium notatum, the mold from which penicillin ismold from which penicillin is derived:
1928: first discovered by Alexander Fleming
1941: first tried on human
Antibiotics: soluble substancesAntibiotics: soluble substances (often derived from molds or bacteria) that inhibit the growth of other microorganism
https://www countway harvard edu/chm/rarebooks/exhibits/stones/scans/mold jpg
Some bacteria cell walls are made of mucoprotein polymersPenicillin prevents crosslinking between protein monomers and therefore
https://www.countway.harvard.edu/chm/rarebooks/exhibits/stones/scans/mold.jpg
p g pcell wall synthesis.
Cells of higher animals (including human) do not have mucoprotein cell walls
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Antibiotics: penicillins
There are many penicillins
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Other antibacterial drugs
Fluoroquinoloneuo oqu o o e
bind to bacterial
inhibitsribosomes inhibitsbacterial DNAreplication
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Viruses
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VirusesDNA viruses (DNA/proteins)
enter host cell direct it to make viral proteinse te ost ce d ect t to a e a p ote s
RNA viruses (RNA/proteins)RNA viruses (RNA/proteins)
enter host cell replicate viral RNA induce synthesis of viral proteinssynthesis of viral proteins
R t i (RNA/ t i )Retroviruses (RNA/proteins)
enter host cell synthesize DNA from the RNA (reverse transcriptase) synthesis of viral(reverse transcriptase) synthesis of viral proteins
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Anti-Viral Drugs
HIV drugs:•Nucleoside analogs (AZT)Nucleoside analogs (AZT)•Reverse transcriptase
inhibitors•Protease inhibitors•Protease inhibitors
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Anti-cancer drug:f CDiscovery of Cisplatin
1845 i di i di hl l ti (II) ( i l ti ) fi t th i d• 1845: cis-diaminedichloroplatinum(II) (cisplatin) first synthesized• 1965: Barnett Rosenberg, inhibition of cell growth by cisplatin• 1970: Cisplatin prevents DNA transcription.
1972 Cli i l t i l f i l ti• 1972: Clinical trials of cisplatin.
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Anti-Cancer drugsgProblem: How to selectively kill cells
One solution: target rapidly dividing cells (antimetabolites)
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Drug DesignDrug Design
• What is a drug? How do they work?What is a drug? How do they work?• What features does a drug need to have?
For efficacy?• For efficacy?• For safety?• For cost-effectiveness?For cost effectiveness?
• How do we find/invent/improve drugs?
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TerminologyTerminology• Target: the biomolecule, g
complex, cell, etc. that the drug is meant to impact
• Library: a large collection of substances that may be useable as drugs
• Hit: a substance that gives the desired result during screening; a potential drug
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Drug discovery/development
E l 1980’Rational drug design
Early 1980’sg g
or Computer aided design (CAD)
Specificity• How do we achieve specificity?
H d h ifi it ?• How do we enhance specificity?
• What targets are we good at?
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Structure-based CAD
Structure ofStructure of working drugs
Chemistry
Modeling
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Enhancing specificityg p y• use proteins as drugs
• antisense (nucleic acids)
• structure-based drug design
• SCREENING
Ad ances in speed q alit and di ersitAdvances in speed, quality, and diversity
• High-throughput techniques
• Combinatorial libraries
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Targetsg
• enzymes• enzymes
• dimeric/domain recognitionWhat we’re • antibodies
• nucleic acids
What we regood at
• multimeric complexes
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High throughput screeningHigh-throughput screeningRational design requires lots of supporting data…
Instead, screen EVERYTHING.
Modern advances:• robotics• library developmenty p• information systems• microvolume chemistry• combinatorial library development• combinatorial library development
1990: 100 compounds/week2003: 100,000 compounds/DAY
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Modern drug discoveryg y
Target ID Hit Target HitTarget ID generation validation development
Choice VerificationChoiceof
library
VerificationBioinformatics Bioassay
Bioassay Choicef
yof
libraryProteomics
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High-throughput screeningHigh throughput screening (HTS)
• Discovery• Hit developmentApplications• Preliminary assessment of
metabolism & toxicity
pp
• Test substance supplyComponents • Bioassay development & implementation
• Informatics
Components
• Informatics
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Test substance supplyTest substance supply• Library development• Combinatorial chemistry• Natural products
St t b d d i• Structure-based design
Define targetdimensions
Computationalanal sis
Use relevantlibraries
Optimizedimensions analysis libraries
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Bioassay developmentBioassay development• Whole animals• Tissue Th h tTissue• Cellular function• Protein function
Cost
Relevance
Throughput
Specificity• Gene expression• Genome sequence
Relevance Specificity
Define targetdimensions
Computationalanalysis
Use relevantlibraries
Optimize
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InformaticsInformatics
• StorageStorage
• Retrieval
• Cross-referencingCross referencing
D fiDefine targetdimensions
Computationalanalysis
Use relevantlibraries
Optimize
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Another big challenge: d d lidrug delivery
http://www.pharmj.com/editorial/19990828/pictures/parenteralFig5.gif