MODULE 1: INTRODUCTION DEVELOPMENT IN CHEMISTRY

5000 years ago: • DIETHYL ETHER (19505)

• Disease has been recognized as an ✓ “Sweet oil of vitriol”
enemy of human kind. It is an affliction
by the gods. • NITROUS OXIDE
• Egyptian therapies focused on purging
✓ Stupefying
the affliction; appeasing dieties
agent
• Greeks became essentially theoretical
following four basic concepts humours • AMYL NITRITE
– black bile, yellow bile, blood, phlegm
became the FRAMEWORK OF HEALTH ✓ First therapeutic drug to come
AND DISEASE.
from synthetic chemistry
• Greek medicine placed a rather little
(Gunthrie, 1859)
emphasis on herbal remedies. It was in
the mid-19th century that chemistry and ✓ Vasodilating effects (Brunton, 1864)
biology advanced sufficiently.
• ANILINE V
19th Century:
✓ Precursor for mauvein (an accidental
• Control of scurvy (Lind, 1973) chemical discovery by Perkin for
• Vaccination (Jenner, 1798) supposedly quinine, 1865)
• Surgical infections using aseptic
techniques (Semmelweis, 1861) • ESTABLISHMENT OF RULES OF VALENCY
• British Pharmacopeia (1864)
• BENZENE (Kekule, 1865)
Late 19th Century:
• EVOLVING SCIENCE OF BIOMEDICINE
• EMERGENCE OF SYNTHETIC ORGANIC
CHEMISTRY
• DEVELOPMENT OF CHEMICAL
INDUSTRY IN EUROPE

DEVELOPMENTS IN BIOMEDICINE

TURN THIS AMBITIOUS NEW INDUSTRY INTO A

SOURCE OF HUMAN BENEFIT RATHER THAN A
CORPORATE PROFIT, IT REQUIRED 2 THINGS:

PRINCIPLES OF BIOMEDICINE (part

PHARMACOLOGY) – understanding how
disease and drugs work respectively
PRINCIPLES OF CHEMISTRY – going beyond
colour, crystallinity, but an understanding of the
structure and properties of molecules and how
to synthesize them in the laboratory.
THE INDUSTY ENTERS THE 20TH CENTURY:
1. Antipyretics
2. Chloral hydrate – first non-volatile
CNS depressant
3. Barbitone – by Von Mering
4. Urea
5. Procaine – by Einthorn; first local
anesthetic drug
6. Cocaine – had a local anesthetic
action in the eye; Simund Freud
DISCERNED 3 MAIN ROUTES OF DRUG
DISCOVERY:
1. Chemistry-driven approaches
2. Target – driven approaches
3. Accidental clinical discoveries
Streptomycin (1949), Vincristine
and Vinblastine (1958),
Paclitaxel (1971), Ciclosporin
(1972), Tacrolimus (1993),
Mevastatin (1976)
2. TARGET – driven drug discovery
• Concept of CHEMOTHERAPY
• Paul Ehrlich is the first
“modernist” who defined the
principles of drug specificity in
terms of specific interaction
between a drug molecule and a
target molecule.
• “Corpora non agunt nisi
fixata”
• Chemistry remained empiric
for many years.
• “Magic bullet”

1. CHEMISTRY - driven drug discovery

A. Synthetic chemistry
• model in the early part of the 20th
century
• Key discipline in drug discovery;
prevailed for 50 years
• Research management was largely
• Drugs produced: benzodiazepines,
tranquilizers, antiepileptic drugs,
antihypertensive, antipsychotics.
• Classification of drugs is based on the
chemical structure rather than MOA
• Phenobarbital incident,” “Phenytoin”

B. Natural product
• “Love-hate” relationship
• Pharmaceutical industry has
difficulty in synthesizing
structures
• Natural products remain
significant source of drugs.
• Examples: Penicillin (1929), Fig. Sulfonamide dynasty
Chloramphenicol (1947),
Tetracycline (1948),
ANTIMETABOLITE PRINCIPLES the Safety of Drugs; All new drugs has
• By Hitching and Elions in 1944 to be submitted for approval before
• Interest in the synthesis of folic acid, clinical trials and market release;
purines, and pyrimidines as Medicines Act (closed the loophole) –
chemotherapeutic agents added efficacy
• Identified dihydrofolate reductase
which is necessary for DNA synthesis. MODULE 2: BIOLOGY OF DISEASE
Pyrimidine analogues inhibited the
enzyme
Mission of the Pharmaceutical Research
• Emergent drugs include:
Companies:
Pyrimethamine, Trimethoprim, 6-
mercaptopurine, Azathioprine, - Understand a disease to bring safe
Aciclovir, Zidovudine and effective new treatment to
patients.
JAMES BLACK AND RECEPTOR – TARGETED
DRUGS TARGETS – a single molecule such as gene
1. Ligand – receptor interactions or protein which is involved in a particular
• Drug antagonism disease.
• Classes of receptors have
varied effects
2. Beta-adrenoreceptor blocking agent
• Pronethalol (1960) – toxic
• Propranolol (1964)
3. H2-receptor antagonist
• Burimamide (1972)
• Cimetidine

3. ACCIDENTAL CLINICAL DISCOVERIES - To establish that product.

1. Digitalis – in treating dropsy
2. Antidysrythmic effect of quinine
3. Amphetamine to treat ADHD
4. Laborit’s discovery of Phenothiazine
5. Promethazine causing sedation
- First step is the pre discovery to drug
discovery up until the last phase
where in there is post marketing
surveillance or pharmacovigilance.

EVENTS LEADING TO ESTABLISHMENT OF

REGULATORY PROCESS
• 1900s - system of “prescription only”
medicines; what info should be on the
label; system of “what cures”;
controlling of addictive substances
• 1937 – diethylene glycol caused death;
demonstrated the need for safety
• 1960 – Thalidomide disaster; Chemie
Grunenthal; UK began to follow US
regulatory laws in safety; urgent
reappraisal because of the incident
• 1963 – establishment of Commission on
 3 to 6 years

DEVELOPMENT:
6-7 years

DRUG DISCOVERY AND PRE-CLINICAL

- Scientific minds
- High sophisticated technology
- Complex project management
- Persistence
- Luck
0.5 to 2 years
*These processes are the reasons why so
many compounds do not make it and some
company stops.

*Some research for natural products, they

would find the medicinal agents or the
structure of medicinal product or herbal
products to be build in structure and some
of it are not easily synthesize or isolated and
purified.

• 1 APPROVED DRUG IN THE MARKET

PROMISING CANDIDATE DRUG TO TEST
Average cost of research and development PEOPLE
is 800 million to 1 billion USD.
1. TARGET IDENTIFICATION
DISCOVERY: - Choose a molecule to target a drug
Pre- discovery which is a single molecule a gene or
Goal: Understand the disease and protein that is involved in a particular
choose a target molecule disease. We should also identify if this
How: Scientist in pharmaceutical target molecule is druggable
research companies, government, (compound should be able to bind to
academic contribute to basic the target to elicit the effect)
research
2. TARGET VALIDATION
- Several targets will now undergo
validation. They will test the target and
 confirm its role to the disease. This *The design principle in this course, starts
means that TV is very crucial to help from Lead Optimization.
scientist avoid useless research that led
to dead ends. 6. PRE- CLINICAL TESTING
- Lab and animal testing is used to determine if
3. DRUG DISCOVERY the drug is safe and enough for human testing.
- Finding a molecule particularly a lead
compound that could become drug.
- The discovery for search for drug to
take effect or elicit action to the target
starts on this step. Molecule will turn
into lead compound, alter the disease.

WAYS TO FIND A LEAD COMPOUND:

1. By nature – come from bacteria,
soil, or plants.
2. Books – scientist can create
molecule from scratch through
sophisticated modeling to predict
what molecule might work.
3. HTS (high throughput screening) –
use of advances in robotics and
computational power to allow
researches to proceed/ test
hundreds of thousand compounds
against the target.
4. Biotechnology – genetically
engineer living system to produce
the biological molecule. PRE DISCOVERY
“Understanding the disease” -> “determine
the underlying cause”
4. EARLY SAFETY TESTS
- As early as the drug discovery part, lead *Find an intervention for that disease
compound goes under series of test and to
determine if they will be pharmacokinetically PARAMETERS (we need to consider)
compatible (absorbed into the bloodstream, 1. How genes are altered
distributed to the proper site of action, and be 2. How that affects the proteins they
metabolized, successfully excreted from the
encode
body and no demonstration of toxic in the body)
3. How those proteins interact with
each other in living cells
5. LEAD OPTIMIZATION
4. How affected cells change specific
- Alter the structure of lead candidates to
improve properties. The research will take tissue
consideration into consideration, formulation, 5. How the disease affects the entire
reactive ingredients, drug delivery system, and patient.
the design.
* The basis for treating the problem.
* Researcher would should know to
sequence human genome.

* This is important for them to know the

origins of proteins they code for gives
them a full catalog of the options. And that
options will be consider as potential target
for new drugs and overall, they have the list
of genes are scientist said that do not know
how they all interact and which are involved in
the disease hence a process of drug discovery
follows starting from the very first step which
is the target identification.

HEALTH
• A state of complete physical,
mental, and social well-being and
not merely the absence of disease
(WHO)
• Health consists in our functioning in
conformity with our natural design
with respect to survival and
reproduction to survival and
reproduction as determined by
natural selection. (Other
philosophers)
• It is a dynamic state of well being
characterized by physical, mental,
and social potential which satisfies
the demands of life commensurate
with age, culture, and personal
responsibility. (Bircher, 2005)
DISEASE
• “Deviation from normality” and
“dysfunction”
• “etiology” and “phenomenology”
• This is very difficult to define
(however researcher and scientist
had difficulty on defining this,
because of different factors to
consider.)
FACTORS:
1. Naturalistic view “observation-
based”
o Disease have defining
characteristic either
structural, biochemical, or
physiological.
2. Normative view “value-base”
o Disease that individual or
society finds disagreeable (i.
e., disvalues) or harmful
o Manifestation of social
intolerance or malfunction”
o Example: in early times,
masturbation was deemed to
be disvalued or harmful.
• Sates of affairs are called disease
when they are due to physiological
or psychological process that are
typically cause states of disability,
pain, or deformity and are generally
held to be below acceptable
physiological or psychological norm
(Caplan et. Al, 1981)
 AIMS OF THERAPEUTICS
1. Minimize disvalue associated with CONCEPTS:
disease
2. For intervention • The researchers should aim to quantify
disease related disvalue and therapeutic
benefit in economic terms. At the same time
WHAT IS THE IMPACT IN in pharmacoepidemiology, assess the
PHARMACEUTICAAL INDUSTY? impact of disease and therapy for the
population not just individual patient.
1. Labeling of borderline conditions will
merit therapeutic interventions.
2. Pharmaceutical industries promote
recognition of questionable
disorders such as phobia, etc.
3. Therapeutic intervention is NOT
RESTRICTED TO TREATMENT AND
PREVENTION OF DISEASE.

• LIFESTYLE DRUGS
• COSMETICS
• PRODUCTS
DRUG DISCOVERY PHASE: LEAD FINDING – starting point.
Lead Finding and Lead Optimization
Recall:

Concepts in target identification and validation

– there are several ways by which researchers
can screen a target. They can analyze the
pathophysiology; they can also analyze using
the mechanism of action. There is also highly
automated process, scrutinizing the different
types of genes in the body. And somehow you
can use gene by trolling it to classified those
disease gene, druggable genes, and disease
modifying genes.

We have mentioned that those modifying genes
are most the druggable genes.
Druggable genes – they have a binding site; they
can also accommodate lead compound.
• There are 10 million and some data
have 70 million compounds registered
in the chemical abstract survey data
base. And total number of possible
compounds to consider as drug
candidate is nearly infinite.

The question really is, where to start or how do

we find a starting point.

- Most of the researchers would usually

start with Lipinski’s rule of 5. It is so
called 5 not because they would have
another parameter and it is multiples of
5.
The next step involves creating biological assays
Lipinski’s Rule of 5 – other name is “Pfizer’s rule
capable of detecting substances which can
of five” or “rule of thumb” (to evaluate drug
modify the target.
likeness)
• So once the target of interest is already
CRITERIA FOR SUITABLE DRUG:
been identified, the reminder of
research is essentially acquest to
identify a single compound. So, we
narrow it down to one compound that
is suitable to use in the clinical setting.
• That is very difficult because, currently
there are plenty of possible compound - Lipophilicity usually express in partition
that can be use. coefficient and p equals to water/
aqueous over the n-octanol (the result
must >5)
EXAMPLE OF HOW THEY EVALUATE LIPINSKI’S: - They would target the same enzyme,
HMG- COA Reductase.
Figure 1: Acyclovir

- The same scenario also, where in they

- It is an antiviral drug. do not have same structure but they
- Molar mass: 200 have the same target and
- Lipophilicity: - 0.1 pharmacologic action of being an
- To get the hydrogen bond donors, inhibitor. They target the PDE- 5.
compute for sum of OH + NH.
So, in the structure, it has 3 hydrogen
bond donors.
- It has 8 hydrogen bond acceptors.

The structure meets the criteria. SCREENING PROCESS

CHALLENGE AMIDST PRESENCE OF LIPINSKI’S

RULE OF 5

✓ Exception to this rule are natural

products
- Because natural products have light • Principle of Z- Factor: the higher z-
structures and they are very difficult to factor of the compound, or if it greater
isolate. Hence, the structure is very than 1 SHOULD NOT BE CONSIDERED.
hard to identify.
✓ Drugs interacting t the same target may
have very little structural overlap.

- In combinatorial libraries – uses

robotics system.
 - 50, 000 to 100,000 screened per day.

GENERAL METHODS OF SCREENING

- It is more practical. Because you just

must design a certain model to be your
reference.
- Ligand based (structure activity data)
- Structure based (docking approach –
- The process in Physical HTS is depend this is 3D structure of biological target
on what the selection of your library is. that used to dock candidate and rank
- The researcher used Focused Libraries. them based on the binding affinity)

Library – selection of compounds.

The higher the docking score, the better
compound.

How to select a library to screen?

✓ Random Screening
o All possible drugs are screened
against a target.
✓ Focused Screening
o A limited number are selected
for screening
o Successful in hit strategy
identification.

THE KEY POINTS IN PHYSICAL HTS:

• Possibility of false positive and false

negative
• Handling reagents
• Degradation of samples/ghost samples
– masyado nang matagal sa library, and
yung material nila or structure ay nag
iba na.

Focused Screening – only biologically active
you’ll be screening.
- 1478 and 58, 317 compounds will
undergo both Virtual and physical HTS
Screening.
- And when you need further
optimization, that is the time you will
have only one compound that will fit to
the criteria.
DRAWBACKS OF VIRTUAL HTS
1. Prediction is based on model systems
and not on actual data.
2. Virtual HITD should still be physically
validated in biological screening to
confirm if predictions are
representatives of the real system.
“HIT” Drug Discovery
- A successful screening should produce a
subset of potential hit compound. That
will need to be examine in order to
determined if further investigations are
needed.
- If hit is already identified, it is now the
Drug discovery or start of finding drug.
(Bale and natira doon sa 10 compounds in
the diagram are what we call Hit
compound)
Further concerns after hit is identified:
✓ Structural class?
✓ Structure-activity relationship?
✓ Patent issue?
LEAD OPTIMIZATION
Once the initial HIT compounds have been
identified, confirmed and a compound class has
been selected for further study, an ITERATIVE
process begins.
o Iterative process – a repeated cycle of
acquisition, biological screening, data
evaluation, and potency of the
compound.
GOAL: Determine

1. Potency
2. Other properties of it.

- If the compound has flaws, it should be

eliminated or removed ASAP.
- Pharmacokinetics Studies covers the
ADME
 - When all these criteria are met,
including the Lipinski’s rule of 5 and
passing all the gates. We can now move
to the next step, pre-clinical
- Aqueous Solubility: has a direct effect
development. We can formulate to
on absorption. It must be soluble to
dosage form, and can administered to
pass the membranes.
animal for pre-clinical studies.

- Permeability: a very significant issue.

This will determine success or failure of
the product.

- Blood Brain Barrier penetration: is for

most CNS drugs or CNS indication.

- Metabolic Stability: once in goes in our

body, tama lang ang metabolic rate
same goes with plasma ang solution
stability.

- CYP 450 inhibition: enzyme found in the

liver. It may slow the metabolism/ drug-
drug interaction.

- Pgp Efflux: dapat sakto lang ang amount

so that compound permeant in the
system.