Biochemical Pharmacology

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Biochemical Pharmacology

• What is it?
• A fancy way of saying pharmacology
• A phrase to hide the fact that we are sneaking a
  subject of medical interest into the UW
  biochemistry curriculum
• An indication that we are not going to discuss
  prescriptions for your grandmothers aching knee
• What is it not?
• A claim that we do understand the mechanism of
  action of each practically useful drug in
  biochemical terms
• A claim that enzyme mechanisms and receptor
  structures, or even cell biology are sufficient
  to understand drug action in the human body

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What are drugs?
Or, more precisely, do they have anything in
common at all? 1. The smallest drug
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2. A large drug molecule
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3. More typical sizes of drug molecules
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Target molecules of drug action The angiotensin
pathway
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Drug targets in the angiotensin pathway
N-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile
-His-Asn- ?
Renin
Angiotensin I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

• Renin Enzyme inhibitors prevent the production
  of angiotensin I

Example Remikiren
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Drug targets in the angiotensin pathway
Angiotensin I
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
Converting enzyme
Angiotensin II
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

• Converting enzyme Enzyme inhibitors prevent the
  production of angiotensin II, the active
  mediator.

Example Enalapril
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Drug targets in the angiotensin pathway
Angiotensin II
Saralasin
vascular smooth muscle cell
Receptor
response (increased blood pressure)
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
Angiotensin II
Sar-Arg-Val-Tyr-Val-His-Pro-Ala
Saralasin
(Sarcosine N-methylglycine)
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Drugs and physiological mediators (1)
Angiotensin II
vascular smooth muscle cell
Receptor
response (increased blood pressure)
Angiotensin II
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
Saralasin
Sar-Arg-Val-Tyr-Val-His-Pro-Ala
(Sarcosine N-methylglycine)
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Non-peptide inhibitors of peptide receptors
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Drugs and physiological mediators
Histamine
stomach mucosal epithelial cell
Receptor
response HCl secretion
ulcer
Histamine
Cimetidine
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Histamine receptor subtypes
Histamine
Allergic reaction
H1 receptor
H2 receptor
Ulcer
Cimetidine
Cyclizine
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Drug discovery and development strategies

• Rational design. Example HIV protease inhibitor
  (saquinavir)

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Drug discovery and development strategies

• Rational design. Example HIV protease inhibitor
  (saquinavir)

• Analyze biological function The protease is
  essential for viral multiplication
• Obtain crystal structure of enzyme, tailor
  inhibitors to fit into active site
• Test and modify, take to clinical testing and
  application

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Drug discovery and development strategies

• Brute force Example Prontosil rubrum, the
  first sulfonamide antimicrobial agent

• Systematically test every new (or old) compound
  for drug activity no matter which purpose it
  was designed for
• If you stumble upon something, figure out how it
  works

Prontosil rubrum
Sulfanilamide, the active metabolite
p-Aminobenzoic acid, a precursor of folic acid in
bacteria
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Drug discovery and development strategies

• Traditional medicine. Example Atropine (Atropa
  belladonna)

• Isolate the active components from
  therapeutically useful and / or toxic plants
• Elucidate structure, mode of action
• Create novel derivatives with improved properties

Acetylcholine
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Drug discovery and development strategies

• Mere chance. Example Penicillin (Penicillium
  notatum)

• Forget to properly cover your petri dish
• Find a mold that kills bacteria (Sir Alexander
  Fleming, 1928)
• Wait until somebody purifies the active
  ingredient and makes it available for clinical
  use (Florey and Chain, 1942)

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Commercial drug development
In vitro studies
Isolate / synthesize a lead compound (a
candidate drug) vary and optimize
Animal testing
Test efficacy, toxicity, selectivity,
pharmacokinetics
Clinical testing
Test efficacy, toxicity, selectivity,
pharmacokinetics Phase 1 Limited series of
healthy volunteers Phase 2 Actual patients with
the corresponding disease Phase 3 Double-blind
studies against placebo or reference treatment
Approval
Review by the authorities be ready to expend
bribes at this stage
Marketing
Patents expire in 15-20 years (varies with
country) after that, generic drugs tend to take
out market share