[PHA 6115 LEC] INTRO TO PHARMACEUTICAL AND MEDICINAL ORGANIC CHEM

Metabolism

-Conversion of the active drug molecule to inactive products ("metabolites"), waiting excretion
-Most drug metabolism is done by the liver

CHEMISTRY IN PHARMACY

-"Almost all the drug in the market is an organic compound."
-Organic chemistry is vital in further pharmacy studies.
-Organic structures and organic compound nomenclature are important concepts to remember

"Almost all the drug in the market is an____."

organic compound

Organic chemistry is vital in

further pharmacy studies.

____are important concepts to remember

Organic structures and organic compound nomenclature

Open-chain

not cyclic or linear structures

Cyclic

Ring structure

Cyclic can be classified based on...

- # of rings
- ring atoms

# of rings

monocyclic, bicyclic

Ring atoms

-homocyclic, heterocyclic

Conjugated

contains 2 or more C-C double bonds separated by single bonds (alternating)

Saturated

contains C-C bonds which are purely single bonds

Unsaturated

contains at least 1 C-C double or triple bond

Alpha Carbon

carbon atom directly attached to a functional group

Vinylic/Olefinic Carbon

carbon atom directly holding a double bond

Allylic Carbon

carbon atom positioned next to a vinylic carbon

Benzylic Carbon

carbon atom positioned next to a benzene

Ortho/Meta/Para

1,2 / 1,3 / 1,4 respective patterns around a benzene ring

RELEVANT CHEMICAL PRINCIPLES

-polarity and solubility
-Acidic and Basic property
-stereoisomerism

Mechanism of Action (MoA)

How exactly a drug works

Drug of Action (DoA)

How long a drug works

Onset of action

Time it takes before the drug takes exhibits an effect

Indication

The approved use of a drug

Adverse Drug Reaction (ADR)

Unwanted effects of the drugs including side effects

Potency

Dose required to exhibit an effect

Lower dose= higher potency

Efficacy

Actual level of a drug's effect

PHARMACOKINETICS

refers to the course taken by the drug once inside the human body

Pharmacokinetics (PK)

"what the body does to the drug

4 FUNDAMENTAL PROCESSES OF PHARMACOKINETICS (ADME)

-absorption
-distribution
-metabolism
-excretion

Absorption

Entry of the drug from site of administration to the bloodstream

Distribution

Travel of drug from bloodstream to different tissues and organs

Most drug metabolism is done by the

liver

Excretion

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

Metabolism and excretion are often grouped under the word

"elimination"

IONIZATION OF DRUGS

can affect absorption especially that most drugs are taken orally

Unionized

- non-polar, uncharged, lipophilic

Ionized

- polar, charged, hydrophilic

Only _____ are absorbed through the lipid layer between GIT and bloodstream

lipophilic drugs

Only ______ are distributed through the bloodstream as the blood acts as an aqueous medium

hydrophilic drugs

Drug____ across a lipid layer between GIT and bloodstream is possible if the drug is lipophilic.

ABSORPTION

Drug ____ along the bloodstream requires that the drug be somehow hydrophilic.

DISTRIBUTION

Balance is between _____ is a must for a drug to be fully effective.

hydrophilicity and lipophilicity

PHARMACODYNAMICS

refers to the physiologic effect resulting from the drug-receptor binding

PHARMACODYNAMICS (PD)

"what the drug does to the body.

Absorbed drugs must find its "target molecule" —

receptors, and bind to it effectively to elicit a response/effect.

After achieving drug-receptor binding, it will result into

the target biologic response

Occupancy

The no. of receptors bound is directly proportional to biologic response.

Rate

The response is related to the times the drug binds to the receptor per unit time.

Induced-Fit

The drug reaches inactive receptors and changes receptor conformation causing better drug binding and biologic response.

Macromolecular Perturbation

This is a combination of the rate and induced-fit theory

Activation-Aggregation

This states that receptors are always in equilibrium for active and inactive sites and agonist/antagonist can only shift this equilibrium

DRUG ACTION

generalized into two categories based on their reaction with the target molecule (receptor):

Agonist

drugs that activate/increase the activity of the receptor

Antagonist

drugs that inhibit/decrease the activity of the receptor

DRUG DISCOVERY AND MEDICINAL CHEMISTRY

The is no perfect drug and all drugs have issues that can be an opportunity for improvement which results to several "options" in managing diseases

3 PARTS OF DRUG DISCOVERY AND MEDICINAL CHEMISTRY

discovery, development, delivery

DRUG DISCOVERY

-starts at conceptualization of new drug research (several dozens to millions of different compounds).
-Numerous stages to filter them out using computational or laboratory tests (no living creatures)
-Ideas; to be further studied

drug discovery starts at

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

drug discovery has numerous stages to ___

filter them out using computational or laboratory tests (no living creatures)

DRUG DEVELOPMENT

-gets molecules from drug discovery, tests in animals, then in humans, and (hopefully) approval for marketing
-occurs in span of years, from discovery to delivery (madali/mabilis na yung 10 years)
-Clinical trials (phase 1-4)

HITS

- first filters

LEADS

- more filters

Drug Candidate

- best ones among the filters

2nd step of drug development is approximately

6 years

steps indrug development

-target id and validation
-hit generation
-lead gen and optimization

Target ID & Validation

-link disease and target
-biomarkers
-high throughput screening
-rational design
-in silicon screening

Hit Generation

-hits confirmation
-potency and cytotoxicity
-prelim animal efficacy
-initial SAR

Lead Gen & Optimization

-potency studies
-selectivity studies
-PK-ADME- tox properties
-SAR pharmacophore modeling

DRUG DELIVERY

testing, analytical quality control for quality checking, regulatory purposes, regulatory approval

MEDICINAL CHEMISTRY

broad but essential are of chemistry required to understand the process of drug discovery and explain the mechanism of drug action

in drug discovery, medicinal chemistry refers to

technologies and laboratory experiments performed to find the best hits/leads/drug candidates

In drug action, medicinal chemistry looks at the

structure of a drug structure and analyzing its activity when administer to humans or other organisms — structure-activity relationship (SAR)

Structure-Activity Relationship (SAR)

this is the correlation between the drug structure and its effect on the body

SAR is the

practical side of medicinal chemistry since analysis of the structure alone can tell us a lot of things about a drug. In SAR, similar structures exhibit similar actions

PHARMACOPHORE

a portion of a drug molecule that is responsible for its activity

PHARMACOPHORE serves as

the "face" of the molecule that interacts with a target receptor

PHARMACOPHORE should remain unchanged to?

retain the drug's activity, but the other components of the structure can be modified to improve the drug's PK.

Bioisosteres

functional groups or fragments which looks like and are as large as an original component of a drug structure.

Bioisosteres usually

substituted for an original component in the hopes of improving the SAR of a drug.