Development mol drug

DEVELOPMENT
OF MOLECULE
INTO
DRUG
PRESENTED BY:
SWATI SARIN
ICRI, Dehradun

What is a drug?
• Any chemical compound - sugar ???
• Anything which produces a change in
the body - an axe ???
• Define by characteristics:
1. use or potential use in diagnosis or
treatment of disease
2. selective in their actions

• A substance used in the diagnosis, treatment, or
prevention of a disease or as a component of a
medication recognized or defined by the U.S.
Food, Drug, and Cosmetic Act.
• A drug is any chemical or biological
substance, synthetic or non-synthetic
DRUG

SOURCES OF DRUGS
Animal insulin (pig, cow)
growth hormone (man)
Plant digitalis (digitalis purpurea)
morphine (papaver somniferum)
Inorganic arsenic
lithium
Synthetic chemical (propranolol)
biological – bacteria-(penicillin)
biotechnology-RDT- (human insulin)

Why are new drugs needed?
UNMET MEDICAL NEED
new diseases (AIDS, Alzheimer’s, obesity)
 low efficacy (dementia, cancer)
 side effects (antidepressants, antipsychotics)
downstream health costs; (Alzheimer’s, spinal injury)
 cost of therapy; (Interleukins)
 costs to individual/country

HISTORY
• 1557, Renaissance surgeon conducted first clinical trial unintentionally
using turpentine, rose oil, egg yolk to prevent treatment to battlefield
wounds
▫ New treatment was more effective.
• 1747, James Lind, Father of clinical trails first to introduce control groups
in his exp.
▫ Documented that citrus fruits could prevent scurvy.
• Concept of study design began in 19th century.
▫ 1863 placebos were used for the first time
▫ 1923 idea of randomization was introduced
• 1948 first randomized trial with blinding was conducted by Medical
Research Council for use of streptomycin to treat pulmonary tuberculosis
• Since 1945, ethical impact of clinical trial gained importance resulting in
strict regulations of medical experiments on human subjects
• 1947, Nuremberg code
• 1964, Declaration of Helsinki (amended in
1975, 1983, 1989,1996,2000,2002,2004)

HISTORY- Regulatory
• Earlier drugs and medicines were based on ancient art of pharmacy.
• 19th century, pharmaceutical industry came into being.
Catalyst Event
Sulfanilamide Tragedy
Nazi Physicians Trial
Thalidomide Tragedy
Syphilis Study
Regulatory Milestone
Food, Drug, and Cosmetic Act- 1938 – concept of
testing marketed drugs on human subjects
Nuremberg Code-1947- informed consent by subjects
Kefauver-Harris Amendments-1962- efficacy tests for
new drugs
National Research Act-1974- Commission for
Protection of Human Subjects for Behavioral and
Biochemical Research

HISTORY – regulations cont…
• Drug development is lengthy and costly process.
• FDA review takes upto 2.5 yrs
• 1992- Prescription Drugs User Fee Act – reduced review process from
30 months to 15 months
• 1999, Clinicaltrials.gov founded.
• 2006, FDA approves first cervical cancer vaccine, Gardasil in just 6
mnths as a part of FDA’s new priority review system.

Drug Discovery and Development Process
The Cost of Drug Discovery and Development
 Average cost to discover and develop a new drug = $800 million
Average length of time from discovery to patient = 10-15 years
Only one NCE (new chemical entity) out of 10,000 leads will make
it to launch.
Target
Identification
and
Validation
Assay
Development
Lead
Generation
Hypothesis
Generation
Candidate Development Commercialization
Phase
III
Submit Global
Launch
Global
Optimization
Lead
Optimization
First
Human
Dose
Phase
IA
Phase
IB/II

DRUG DEVELOPMENT
Three phases:
Discovery
Pre clinical
development
Clinical

Drug Discovery & Development
Identify disease
Isolate protein
involved in
disease (2-5 years)
Find a drug effective
against disease protein
(2-5 years)
Preclinical testing
(1-3 years)
Formulation
Human clinical trials
(2-10 years)
Scale-up
FDA approval
(2-3 years)

Technology is impacting this process
Identify disease
Isolate protein
Find drug
Preclinical testing
GENOMICS, PROTEOMICS & BIOPHARM.
HIGH THROUGHPUT SCREENING
MOLECULAR MODELING
VIRTUAL SCREENING
COMBINATORIAL CHEMISTRY
IN VITRO & IN SILICO ADME MODELS
Potentially producing many more targets
and “personalized” targets
Screening up to 100,000 compounds a
day for activity against a target protein
Using a computer to
predict activity
Rapidly producing vast numbers
of compounds
Computer graphics & models help improve activity
Tissue and computer models begin to replace animal testing

High throughput
screening (HTS)
Structure Activity
relationship (SAR)
Phase I
Phase II
Phase III
Phase IV
Drug Candidate development
Toxicology
Pharmacokinetics
ADME

(A). Drug Discovery
I. Choose
a disease
VI.
Market
V. Clinical
Trials
IV.
Optimize
lead
III. Find a
lead
compound
II. Choose
a drug
target

I. Choosing a Disease
• What factors?
▫ Medical
▫ Economic
▫ Geographical
Pharmaceutical companies must make a
profit to exist
Pharmaceutical companies
will, therefore, avoid products with too small
a market (i.e. a disease which only affects a
small subset of the population)
Pharmaceutical companies will also avoid
products that would be consumed by
individuals of lower economic status (i.e. a
disease which only affects third world
countries)
Most research is carried out on diseases
which afflict “first world” countries: (e.g.
cancer, cardiovascular
diseases, depression, diabetes, flu, migraine,

II. Choosing a Drug Target
• What are they?
 Drug Target = specific macromolecule, or biological system, which
the drug will interact with
• How are they discovered?
 Sometimes this can happen through incidental observation…
 From drugs
 From chemical messengers
 Molecular genetics

Identifying a Drug Target (cont.)
 Example: In addition to their being able to inhibit the uptake
of noradrenaline, the older tricyclic antidepressants were
observed to “incidentally” inhibit serotonin uptake. Thus, it was
decided to prepare molecules which could specifically inhibit
serotonin uptake. It wasn’t clear that this would work, but it
eventually resulted in the production of fluoxetine (Prozac).
NH2
N
H
HO
serotonin
O
HN
prozac
N
N
CH3
H3C
Imipramine
(a classical tricyclic antidepressant)
F3C

The mapping of the human genome should help!
• Many medicines (and lead compounds) were isolated from plant sources.
• Having the genetic code for the production of an enzyme or a receptor may
enable us to over-express that protein and determine its structure and
biological function. If it is deemed important to the disease
process, inhibitors (of enzymes), or antagonists or agonists of the receptors
can be prepared through a process called rational drug design.
• Plants and natural sources are not likely to provide the cures to all diseases.
• In a process called “combinatorial chemistry” large numbers of compounds
can be prepared at one time.
Combitorial chemistry

• Multiple targets
• Choosing the Bioassay
In vitro: In an artificial environment, as in a test tube or
culture media
 High throughput screening
 NMR (Nuclear Magnetic resonance)
In vivo: In the living body, referring to tests conducted in
living animals
Ex vivo: Usually refers to doing the test on a tissue taken
from a living organism
Screening perhaps millions of compounds in a corporate
collection to see if any show activity against a certain
disease protein
HIGH THROUPUT SCREENING:

III. Find a Lead Compound
• “lead compound” = structure that has
some activity against the chosen
target, but not yet good enough to be
the drug itself.
• Where?
 Random screening
▫ Synthetic chemicals: already
manufactured by pharmaceutical
companies
▫ Natural products: Plants,
microbes, the marine world,
and animals
Pacific yew tree
Taxol

• Existing drugs
▫ Previously marketed for same disease
▫ Used for other diseases
Using Someone Else’s Lead
Design structure which is similar to existing lead, but different enough to avoid patent restrictions.
Sometimes this can lead to dramatic improvements in biological activity and pharmacokinetic
profile. (e.g. modern penicillins are much better drugs than original discovery).
Enhance a side effect
O
N H
S
O
O
N H
tolbutam ide
N H 2S
O
O
H 2N
sulphanilam ide
(an antibacterial w ith the side effect of
low ering glucose levels in the blood and also
diuretic activity)
(a com pound w hich has been optim ized to only
low er blood glucose levels. U seful in the treatm ent
of T ype II diabetes.)
S
N H
N
O O
S
O
OH 2N
C l
C hlorothiazide
(a com pound w hich has been optim ized to only display diuretic
activity.)

• Existing drugs
• Natural substrate or product
▫ Alter structure:
▫ Use structural similarity to a natural ligand
S
E
ES
P
E
EP
P
E
E + P
E
S
E + S
E

• Existing drugs
• Combinatorial synthesis

• Existing drugs
• Computer-aided design
▫ X-ray crystallography of binding sites
▫ Molecular modeling to design drug
Computer-Assisted Drug Design
If one knows the precise molecular structure of
the target (enzyme or receptor), then one can
use a computer to design a perfectly-fitting
ligand.

• Existing drugs
• Chance : Serendipity
• Example: Penicillin discovery
• Example: development of Viagra to treat erectile dysfunction
N
N
S
O
O
N
N
N
NH
O
O
viagra
(Sildenafil)

• Existing drugs
• Chance
• NMR
Binding Site
Protein

Protein
NO OBSERVABLE BIOLOGICAL EFFECT

13C NMR
C
C
CHCH
CH
CH2
CH2
CH3
CH3

CH2
CH3
13C NMR
C
C
CHCH
CH
CH2
CH3

Protein
Optimize
epitope
Optimize
epitope

Protein
Optimize
epitope
Optimize
epitope
Link

H
N
HO
O
OH
N
O
O
OM e
OM e
M eO
O
O
Me
Epitope A
Epitope B

H
N
HO
O
OH
N
O
O
OM e
OM e
M eO
O
O
Lead compound

• After lead compound is found, but before
optimizing…
▫ Isolate
▫ Purify
▫ Structural confirmation

IV. Optimize Lead Compound
N
OH
OH
CH 3
R O H R O M e
C H 3I
C H 3C O C l
R
O
O
C H 3
C H 3S O 2C l
R S
O
O
C H 3
O
LiA lH 4
R H
Ether
Ester
Alkane
• Structure-activity relationships (SARs)
Alcohol:
•Structure-Activity-Relationship (SAR) = How does the activity change as structure is
systematically altered?
•Identify the “pharmacophore”
pharmacophore = the structural features directly responsible for activity
•Vary structure to improve interactions with target
•This may enable one to prepare a more active molecule
•This may allow the elimination of “excessive” functionality, thus reducing the toxicity
and cost of production of the active material
•This can be done through synthetic modifications
Example: R-OH can be converted to R-OCH3 to see if O-H is involved in an important
interaction

IV. Optimize Lead Compound
1. Variation of alkyl substituents
2. Variation of chain length
ANALOGUE
C
CH 3
CH 3H 3C
van der Waals
interactions
LEAD COMPOUND
CH 3
Hydrophobic
pocket

RECEPTOR
Unused
binding
region
DRUG
RECEPTOR
DRUG
Extra
functional
group
Drug
Extension
3. Extension of structure

Binding Region
(H-Bond)
Binding Region
(for Y)
para Substitution
Binding
site
H
O
Y
meta Substitution
Binding
site
O
H
Y
Weak
H-Bond
Strong
H-Bond
(increased
activity)
Variation of Ring Size and Structure
4. Change in substitution pattern

Hydrophobic regions
R R
R
R
Ring
expansion
Variation of Ring Size and Structure
5. Variation in ring size
6. Variation in ring structure
H
N S

O H
NHM e
O M e
HO O C
Ph
Cl
Drug
OH
NHM ePh Drug
7. Simplification
H
NX
CH3
X NHM e X
NHM e
X
M e
N
X
NM e
X
NHM e
Introducing
rings
8. Rigidification

(B). PRE CLINICAL DEVELOPMENT
 Toxicology
 Pharmacokinetics
 ADME studies
Performed in animal
models
in vitro
 in vivo
 in silico

TOXICOLOGY
Pharmacological effects are same in man as in animals
Toxic effect in species will predict adverse effects in man
Giving high doses in animals improves predictability to man
Systemic toxicology studies
Single dose studies Repeated dose studies
Reproductive toxicology studies
Male fertility Female reproduction & Developmental
studies
Local toxicity studies
Hypersensitivity studies
Genotoxicity studies
Carcinogenicity studies

ADME STUDIES
&
pharmacokinetics
These studies are carried out to reveal the effects of drug
on the body
In vitro
In vivo
In silico

In silico
 In silico is an expression used to mean “performed on computer”.
 In silico research in drug is thought to have the potential to speed
the rate of drug discovery while reducing the need of expensive lab
work and clinical trials.
APPROACHES:
Genomic sequence analysis
Analysis of 3D structure of protein
Biological pathways analysis and
modeling
In silico cell analysis of prokaryotic
and eukaryotic hosts e.g.
E.coli, B.subtilis, yeast etc.
To calculate the ADME/Tox properties
,various software are available:
C2-ADME
TOPKET
GLGOP
Drug Metrix
Bioprint
GestroPlus

Real time in-vivo imaging/biophotonic
technology
• Devp. and devised by xenogen corp.usa
• Brand name IVIS IMAGING SYSTEM
• Creates image or photo data from intact living animal system to study
pharmacological activity
• Ensures more efficient utilization of animal models
• Effective against in-vivo study of cancer, anti-inflammatory,infectious
disease
HOW IT WORKS?
• Requires transgenic animals as (animal models)
• luciferase genes gets incoroporated into other cells
of animal (tagged cell) that tag cell is injected into the
animals and emit light when activated. Anthrax expressing the lungs
&
respiratory tract

IND (Investigational New Drug
Application)
IND- notice of claimed investigational exemption
for a new drug must be filed with regulatory body

(C). CLINICAL DEVELOPMENT
 Phase I
 Phase II
 Phase III
 Phase 1V
A clinical trial is defined as organized research on human
beings intended to provide adequate information on the
drug use as a therapeutic agent on its safety and efficacy.

A clinical trial may be designed to :
• Assess the safety and effectiveness of a new medication or
device
• Assess the safety and effectiveness of a different dose of a
medication than is commonly used
• Assess the safety and effectiveness of an already marketed
medication or device for a new indication
• Assess whether the new medication or device is more effective
for the patient's condition than the already used, standard
medication or device

Phase 0
• Phase 0 is conducted in accordance with the U.S. FDA’s 2006
Guidance on Exploratory Investigational New Drug (IND) Studies.
• Phase 0 trials are also known as human micro dosing studies.
• Distinctive features include the administration of single sub-
therapeutic doses of the study drug to a small number of subjects
(10 to 15) to gather preliminary PK and PD data.
• A Phase 0 study gives no data on safety or efficacy, being by
definition a dose too low to cause any therapeutic effect.

Phase I
• Phase I trials classically are considered ‘‘first in human’’ studies.
• A small (20-100) group of healthy volunteers will be selected.
• Used to assess the safety, tolerability, pharmacokinetics, and
pharmacodynamics of a drug.
• Phase I trials include dose-ranging, also called dose escalation studies
so that the appropriate dose for therapeutic use can be found.
20-100 in Phase I

Phase II
 Phase II trials are performed on larger groups (20-300).
 They are designed to assess how well the drug works, as well as to
continue Phase I safety assessments in a larger group of volunteers
and patients.
 A Phase II trial can last two to three years.
Hundreds in Phase II

• Phase II studies are sometimes divided into:
• Phase IIA
• Phase IIB
• Phase IIA is specifically designed to assess dosing requirements (how
much drug should be given).
• Phase IIB is specifically designed to study efficacy (how well the drug
works at the prescribed dose(s)).

PHASE III
• Also known as therapeutic confirmatory trials
• randomized controlled
• multicenter trials
• on large patient groups (300–3,000 or more depending upon the
disease/medical condition studied)
• Safety ,drug interactions are accessed on a larger scale
• Additional pharmacokinetic data may be obtained.
• Phase III trials are the most expensive
• time-consuming

NDA (New Drug Application)
 The vehicle through which drug sponsors formally
propose that the regulatory body approve a new
pharmaceutical for sale and marketing.
 Form 44
 The data gathered during the animal studies and
human clinical trials of an Investigational new
product become part of the NDA.

Phase IV
• Post marketing survelliance
• Used to describe the research and studies associated with
product safety evaluation after the drug has been approved for
marketing.
• Pms=Pharmacovigilance+Pharmacoeconomics+Pharmaco
epidemiology.
• No fix duration

OBJECTIVES OF PMS
 Confirm the efficacy and safety profile in large populations
during practice
 Detect the unknown adverse drug reaction/s
 Evaluation of over-dosage and treatments
 Identifications of new indications
 Evaluation of new formulations, dosages, durations of
treatment.
 Evaluation in different age groups / types of patients

Development Programme for an NCE
PHASE III PHASE IV
PHASE I
PHASE IPRECLINICAL PHASE II
Product Approval
(NDA/MAA)
Patient studiesEntry to man
(IND / CTA)
None
Healthy subjects
Safety and
tolerability
Genetic toxicity
(in vivo)
Repeat dose
toxicity testing
+
Bioanalysis /
Toxicokinetics
Drug Metabolism
Reproductive
Toxicity Testing
(teratogenicity)
Patients
Small scale
efficacy studies
Patients
Large scale
multicentre
studies
Chronic (long term) toxicity testing
+
Bioanalysis / Toxicokinetics
Reproductive Toxicity Testing
(fertility and pre/post natal)
Carcinogenicity studies
Drug Metabolism
Patients
Large scale
post-marketing
studies
As required
Genetic toxicity
(in vitro)
Single / repeat dose
toxicity studies
+
Bioanalysis /
Toxicokinetics
Safety Pharmacology
Drug Metabolism
Lead candidate
Identified
Non-clinical

REFERENCES
• Gupta S. K; Basic principles of clinical research
and methodology
• gopher://www.ccl.net/00/documents/drug.design.
guide
• http://en.wikipedia.org/wiki/Drug_design

Development mol drug

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