Biochemical Pharmacology
What is it? 1. A fancy way of saying pharmacology 2. A phrase to hide the fact that we are sneaking a subject of medical interest into the UW biochemistry curriculum 3. An indication that we are not going to discuss prescriptions for your grandmother’s aching knee What is it not? 1. A claim that we do understand the mechanism of action of each practically useful drug in biochemical terms 2. A claim that enzyme mechanisms and receptor structures, or even cell biology are sufficient to understand drug action in the human body
What are ‘drugs’?
Or, more precisely, do they have anything in common at all? 1. The smallest drug:
What are ‘drugs’?
2. A large drug molecule:
What are ‘drugs’?
3. More typical sizes of drug molecules:
O S H2 N S O N N N H C H3 O
Acetazolamide
H C HC HC CH H2 CH C H3 O C H2 C H2 H C C O N H O C H C H2 C C H3 H2 C N C C H2 C H C O OH
Enalapril
H C HO C H
H C N H C H
O C C H3
Acetaminophen
Target molecules of drug action (I)
Example: The angiotensin system Angiotensinogen (MW 57000)
N’-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-
Renin
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
Angiotensin I
Converting enzyme
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe Peptidases (degradation)
Angiotensin II
Target molecules of drug action (II)
Angiotensin II
Receptor Phospholipase C (inactive) G-protein (active)
vascular smooth muscle cell PIP2
DAG
G-protein (inactive)
Phospholipase C (active) IP3
Ca++
contraction
blood pressure
Drug targets in the angiotensin pathway (I)
N’-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn- Renin Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu 1.
Angiotensin I
Renin: Enzyme inhibitors prevent the production of angiotensin I
H C HC HC CH CH H2 C H2 C O N H O H C C H2 N H H C C H2 C H H C OH C H2 H2 C C H2 C H2 OH C H H C C H2 C H2
C H3 O
C H2 C H2 C H
Example: Remikiren
H3 C
S C H3 O
N C H N H
CH
Drug targets in the angiotensin pathway (II)
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
Angiotensin I
Converting enzyme
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe 2.
Angiotensin II
Converting enzyme: Enzyme inhibitors prevent the production of angiotensin II, the active mediator.
H C HC HC CH H2 CH C H3 O C H2 C H2 H C C O N H O C H C H2 C C H3 H2 C N C C H2 C H C O OH
Example: Enalapril
Drug targets in the angiotensin pathway (III)
Angiotensin II
vascular smooth muscle cell Receptor
response (increased blood pressure)
N
H N
3.
Angiotensin receptor: Receptor blockers prevent the binding of angiotensin II
N
N
O
Example: Valsartan
HO H3 C
N C H3 O C H3
Drugs and physiological mediators (1)
Angiotensin II vascular smooth muscle cell
Receptor
response (increased blood pressure)
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe
Sar-Arg-Val-Tyr-Val-His-Pro-Ala
(Sarcosine = N-methylglycine)
Angiotensin II
Saralasin
Drugs and physiological mediators (2)
Histamine stomach mucosal epithelial cell
Receptor
response: HCl secretion Histamine
C H2 HN N C H2 N H2
HN
ulcer
C H2 N C H2 N H C NH N H2
Cimetidine
H3 C HN N
C H2
S
C H2
C H2
N H
C N C
N H N
C H3
Drugs and physiological mediators (3)
Histamine
C H2 HN N C H2 N H2
Allergic reaction
H1 receptor
H2 receptor
Ulcer
Cyclizine
HC N N C H3
Cimetidine
H3 C HN N C H2 S C H2 C H2 N H C N C N N H C H3
Drug discovery and development strategies
1. Rational design. Example: HIV protease inhibitors
• 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
Drug discovery and development strategies
2. Brute force: Example: ‘Prontosil rubrum’, the first sulfonamide antimicrobial agent
H C H2 N N N C H C H H C O S O N H2
•
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
N H2
‘Prontosil rubrum’
H C H C O S C H C H O N H2
H2 N
•
Sulfanilamide, the active metabolite
H C O
H C H2 N C H
p-Aminobenzoic acid, a precursor of folic acid in bacteria
C H
OH
Drug discovery and development strategies
3. Traditional medicine. Example: Atropine (Atropa belladonna)
OH
•
Isolate the active components from therapeutically useful and / or toxic plants
C H2
+
C H O
O
N H2
• •
Elucidate structure, mode of action Create novel derivatives with improved properties
H3 C O O C H2 C H2
C H3
+
N C H3
C H3
Acetylcholine
Drug discovery and development strategies
4. 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)
•
Commercial drug development
In vitro studies Isolate / synthesize a ‘lead compound’ (a candidate drug); vary and optimize
Animal testing
Clinical testing
Test efficacy, toxicity, selectivity, ‘pharmacokinetics’
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 Review by the authorities – be ready to expend bribes at this stage Patents expire in 15-20 years (varies with country) – after that, generic drugs tend to take out market share
Approval
Marketing