MED ORG LEC - 02 Introduction to Medicinal Chemistry

Mechanism of Action (MoA)

How exactly the drug works

ex. Cetirizine - blocks histamine receptors

(Pharmacodynamic)

Duration of Action (DoA)

How long the drug works

ex. Paracetamol - 4 to 6 hours

(Pharmacokinetic)

Onset of Action

Time it takes before the drug takes effect

ex. Paracetamol - works after 15 minutes

(Pharmacokinetic)

Indication

Approved use of the drug

ex. Paracetamol - analgesic, antipyretic

Adverse Drug Reaction (ADR)

Unwanted effects of a drug (including side effects)

TRUE

TRUE or FALSE

Not all Adverse Drug Reaction (ADR) are side effects, but all side effects are ADRs.

Potency

Dose required to have effect

(lower dose = more potent)

ex. Drug A (10 mg) vs Drug B (15 mg) = Drug A is more potent

Efficacy

Actual level of the drug’s effect

(measure of its effect)

Pharmacokinetics (PK)

• What the body does to the drug

• ADME

  • Absorption

  • Distribution

  • Metabolism

  • Excretion

Aborption

Entry of the drug from site of administration to the bloodstream

Distribution

Travel of drug from bloodstream to different tissues and organs

Metabolism

Conversion of the active drug molecule to inactive products (metabolites), waiting excretion

Liver

Most drug metabolism is done by the _____.

Excretion

Permanent removal of the inactive metabolites from the body, often via the kidney

Biotransformation

Other name for Metabolism

Elimination

Metabolism and excretion are often grouped under the word “_____”

Unionized

• Nonpolar

• NO charge

• Lipophilic

LUNA (Absorbed)

Ionized

• Polar

• CHARGED

• Hydrophilic

HIPE (Excreted)

Lipophilic (Unionized)

The drug product can only be absorbed by the lipid layer separating the GIT and the bloodstream if it is _____

Hydrophilic (Ionized)

Once in the blood, the drug must somehow be _____ enough to allow it to be distributed

Unionized

Ionized or Unionized

• Acidic pH

• Weak acid

Ionized

Ionized or Unionized

• Basic pH

• Weak acid

Ionized

Ionized or Unionized

• Acidic pH

• Weak base

Unionized

Ionized or Unionized

• Basic pH

• Weak base

Pharmacodynamics (PD)

• What the drug does to the body

• Once absorbed and distributed, the drug must find its target molecule and bind to it, which leads to the effect/response

• The “target molecule” is often a receptor or a transporter/enzyme related to it

• Once receptors and drug response come into play

Agonist

Some drugs that work by improving the activity of the receptor

Antagonist

Some drugs that work by decreasing the activity of the receptor

Drug Discovery and Medicinal Chemistry Process

1. Discovery

2. Development

3. Delivery

Drug Discovery

Starts at conceptualization of new drug research (several dozens to millions of different compounds)

Filters them using:

• Computational Tests (in silico)

• Laboratory Tests (in vitro)

Drug Development

Gets molecules from drug discovery, tests in animals (in vivo), then in humans (clinical trials), and (hopefully) approval for marketing

Hits

First filters

Leads

More filters

Drug Candidates

Best ones (can eventually proceed to drug development)

Medicinal Chemistry

• Chemistry required in drug discovery and understanding the action

• In drug discovery, this refers to the technologies and laboratory experiments done to search for the best hits/leads/drug candidates

• In drug action, this simply involves looking at the structure of a compound and then analyzing its activity on humans or other organisms

Structure-Activity Relationships (SAR)

• Correlation between a drug’s structures and its effects on its body

• Tells us a lot of things about drugs we encounter everyday, so its is the practical side of medicinal chemistry

To find the best features of a drug as much as possible

Why perform Structure-Activity Relationships (SAR) studies?

Through cycles of prediction, synthesis, and experimentation

How to perform Structure-Activity Relationships (SAR) studies?

Pharmacophore

• Portion of a drug molecule that gives it its activity

• “Face” of the molecule that interacts with the target receptor

• It should remain unchanged (to retain PD/activity), but other parts can be changed to improve PK properties

Bioisosteres

A functional group or fragment which looks like/is as large as an original part of the drug

Birth

Using newly-acquired knowledge SAR to figure the PD and PK of a drug candidate (the cycle starts)

Rebirth

• Using already-gathered knowledge on SAR to explain the PD and PK of an approved drug

• Improvements can be recommended (the cycle restarts)