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Drug Discovery Process. BIT 120. ACE Inhibitors. Angiotensin Converting Enzyme (ACE) causes constriction of blood vessels by converting angiotensin from inactive to active form – want to block this enzyme, so blood vessels relax (Better blood flow, lower b.p.)

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ACE Inhibitors

Angiotensin Converting Enzyme (ACE)

causes constriction of blood vessels by converting angiotensin from inactive to active form – want to block this enzyme, so blood vessels relax (Better blood flow, lower b.p.)

Look for inhibitors to other ACE proteins

Class of drugs – end in “pril” – Captopril, etc.


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Discovery ProcessPre-Clinical

Search Public Genome Databases for similar (homologous)

sequences to original ACE gene

Take these snippets and hybridize with genetic material from different tissues

Matches LIGHT up.

Clone the genes that light up


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Find chemical which inhibits this enzyme

DRUG CANDIDATE

Animal Studies

(preclinical studies)


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Some considerations

  • Look at safety in animals – large doses and long term

  • Chronic – long term- asthma, hypertension (need to take drug for life)

  • Acute – short term – for short term illness (e.g., bacterial infection, take antibiotic for 10 days)


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Animal Models

  • Knockout Mice

  • disrupt gene by deliberate mutation – gene blocked at

  • embryo stage

  • Problems

    • Animals may not get disease we get (HIV)

    • Model does not mimic human condition(good model – athero and pigs)

    • PETA – people for the ethical treatment of animals


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Timeline for Discovery and Development

A. Laboratory and animal studies 6 yrs

B. File Investigational New Drug (IND)

to FDA

C. Phases I- III 7 years

D. File New Drug Application (NDA)

at FDA: 1.5 years

E. Phase IV (post approval) 6 years


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Clinical Trials

IND components – Goes into effect after 30 days if FDA says nothing

Previous experiments

Chemical structure

Toxicity in animals


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Purpose

  • Is drug SAFE AND EFFECTIVE???

    • Predict Toxic Effects

    • Determine Safe Dosage

    • Determine efficacy (effectiveness)


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Participant in trial

  • Entry criteria – age, sex, smoking status, other meds

  • Big cities

  • Sign a consent form

  • Voluntary – can withdraw anytime

  • Confidentiality

  • Often paid


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Cost

Cost:

$500 million/drug (dropping due to genomics)

Success Rate

5000 : 1

Total time

15 years chemical drug

10 years biological drug


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Phase I

  • small group of people (20-80)

  • individuals do NOT have disease

  • evaluate its safety; common side effects:

    • Fatigue, nausea, hair loss, vomiting

  • determine a safe dosage range

  • identify side effects

  • 0.5-1.5 years


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Pharmacokinetics

  • How drug is:

    • Absorbed

    • Metabolized

    • Excreted

    • Duration of action


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Phase II

  • larger group of people (100-300)

  • people with disease

  • effectiveness

  • further evaluate its safety

  • dosage

  • 2 years


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Phase III

  • large groups of people (1,000-3,000)

  • to confirm its effectiveness

  • monitor side effects

  • compare it to commonly used treatments

  • Interactions (with other meds)

  • Multicenter trial – many docs; many hospitals


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Phase III

  • May be vs. placebo:

  • Placebo effect: measurable, desirable effect; patients don’t know if on drug or placebo

  • Patient feels better even if on placebo

    • Often seen with antidepressants, antianxiety meds



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Phase IV

  • after the drug or treatment has been marketed

  • collect information about their effect in various populations

  • side effects associated with long-term use.

  • New indications: impt for company to extend its patent protection.

  • Eg. Prozac – antianxiety, approved recently for PMDD (premenstrual dysorphic disorder)


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Issues

Pharmacokinetics

how quickly drug is absorbed

eliminated from body (clearance)

Delivery Problem – injection vs. oral delivery

Do patients develop tolerance?

Pharmacogenetics

Interfere with meds for other diseases – eg. Lower bp

but interfere with med for type II diabetes


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Placebo

  • When don’t you use a placebo?

  • Drug available already to treat disease

  • Unethical to use placebo


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Discovery:

Good Laboratory Practices (GLP)

Development:

Good Manufacturing Practices (GMP)

Standard Operating Practices (SOP)

Documentation, Documentation, Documentation


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