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 disease2. 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 ProcessDrug Discovery and Development Process

The Cost of Drug Discovery and Development Average cost to discover and develop a new drug = $800 millionAverage length of time from discovery to patient = 10-15 yearsOnly one NCE (new chemical entity) out of 10,000 leads will make it to launch.

TargetIdentification

andValidation

Assay Development

LeadGeneration

HypothesisGeneration

Candidate Development Commercialization

PhaseIII

Submit GlobalLaunch

GlobalOptimization

LeadOptimization

FirstHumanDose

PhaseIA

PhaseIB/II

DRUG DEVELOPMENT

Three phases:

Discovery

Pre clinical development

Clinical development

Drug Discovery & DevelopmentIdentify disease

Isolate proteininvolved in disease (2-5 years)

Find a drug effectiveagainst disease protein(2-5 years)

Preclinical testing(1-3 years)

Formulation

Human clinical trials(2-10 years)

Scale-up

FDA approval(2-3 years)

File

IN

D

File

NDA

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 targetsand “personalized” targets

Screening up to 100,000 compounds aday for activity against a target protein

Using a computer topredict activity

Rapidly producing vast numbersof 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 IIPhase IIIPhase IV

Drug Candidate developmentToxicologyPharmacokineticsADME

(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, obesity).

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

NH

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 BioassayIn 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

III. Find a Lead Compound• Existing drugs

▫ Previously marketed for same disease

▫ Used for other diseases

Using Someone Else’s LeadDesign 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

NH

SO

O

NH

tolbutamide

NH2S

O

O

H2N

sulphanilamide

(an antibacterial with the side effect oflowering glucose levels in the blood and alsodiuretic activity)

(a compound which has been optimized to only lower blood glucose levels. Useful in the treatment of Type II diabetes.)

SNH

N

O O

SO

OH2N

Cl

Chlorothiazide

(a compound which has been optimized to only display diureticactivity.)

III. Find a Lead Compound• 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

III. Find a Lead Compound• Existing drugs• Natural substrate or product• Combinatorial synthesis

III. Find a Lead Compound

• Existing drugs• Natural substrate or product• Combinatorial synthesis • 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.

III. Find a Lead Compound

• Existing drugs• Natural substrate or product• Combinatorial synthesis • Computer-aided design• Chance : Serendipity• Example: Penicillin discovery• Example: development of Viagra to treat erectile

dysfunctionN

N

S

O

O

N

N

N

NH

O

O

viagra(Sildenafil)

III. Find a Lead Compound

• Existing drugs• Natural substrate or product• Combinatorial synthesis • Computer-aided design • Chance • NMR

Binding Site

Protein

Protein

NO OBSERVABLE BIOLOGICAL EFFECT

13C NMR

CC

CHCH

CH

CH2

CH2

CH3

CH3

CH2

CH3

13C NMR

CC

CHCH

CH

CH2

CH3

Protein

Optimize epitope

Protein

Optimize epitope

Optimize epitope

Protein

Optimize epitope

Optimize epitope

Link

LEAD COMPOUND

HN

HO

OOH

NO

O

OMeOMe

MeO

O

O

Me

Epitope A

Epitope B

HN

HO

OOH

NO

O

OMeOMe

MeO

O

O

Lead compound

III. Find a Lead Compound

• After lead compound is found, but before optimizing…

▫ Isolate

▫ Purify

▫ Structural confirmation

IV. Optimize Lead Compound

N

OH

OH

CH3

R OH R OMeCH3I

CH3COClR

O

O

CH3

CH3SO2Cl

R SO

O

CH3

O

LiAlH4R 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 modificationsExample: 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

CH3

CH3H3C

van der Waals interactions

LEAD COMPOUND

CH3

Hydrophobicpocket

RECEPTOR

Unusedbindingregion

DRUG

RECEPTOR

DRUGExtrafunctionalgroup

DrugExtension

3. Extension of structure

Binding Region(H-Bond)

Binding Region(for Y)

para Substitution

Bindingsite

HO

Y

meta Substitution

Bindingsite

O

H

Y

WeakH-Bond

StrongH-Bond(increasedactivity)

Variation of Ring Size and Structure

4. Change in substitution pattern

Hydrophobic regions

R R RR

Ringexpansion

Variation of Ring Size and Structure5. Variation in ring size

6. Variation in ring structure

HN S

OH

NHMe

OMe

HOOC

Ph

Cl

Drug

OH

NHMePh Drug

7. Simplification

HNX

CH3

X NHMe X

NHMe

X

MeN

X

NMe

X

NHMe

Introducingrings

8. Rigidification

(B). PRE CLINICAL DEVELOPMENT

Toxicology

Pharmacokinetics

ADME studies

Performed in animal models in vitro in vivo in silico

TOXICOLOGYPharmacological effects are same in man as in

animalsToxic effect in species will predict adverse effects in

manGiving 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 studiesLocal 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 vitroIn vivoIn 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-ADMETOPKETGLGOPDrug MetrixBioprintGestroPlus

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

IND REVIEW PROCESS

(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.

NDA REVIEW PROCESS

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+Pharmacoepidemiology.

• 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 IVPHASE I

PHASE IPHASE IPRECLINICALPRECLINICAL PHASE II

Product Approval (NDA/MAA)

Patient studies

Entry to man(IND / CTA)

NoneNone

Healthy subjects

Safety andtolerability

Healthy subjects

Safety andtolerability

Genetic toxicity(in vivo)

Repeat dose toxicity testing

+Bioanalysis /

Toxicokinetics

Drug Metabolism

Reproductive Toxicity Testing(teratogenicity)

Genetic toxicity(in vivo)

Repeat dose toxicity testing

+Bioanalysis /

Toxicokinetics

Drug Metabolism

Reproductive Toxicity Testing(teratogenicity)

Patients

Small scale efficacy studies

Patients

Small scale efficacy studies

Patients

Large scalemulticentre

studies

Patients

Large scalemulticentre

studies

Chronic (long term) toxicity testing+

Bioanalysis / Toxicokinetics

Reproductive Toxicity Testing (fertility and pre/post natal)

Carcinogenicity studies

Drug Metabolism

Chronic (long term) toxicity testing+

Bioanalysis / Toxicokinetics

Reproductive Toxicity Testing (fertility and pre/post natal)

Carcinogenicity studies

Drug Metabolism

Patients

Large scalepost-marketing

studies

Patients

Large scalepost-marketing

studies

As requiredAs required

Genetic toxicity(in vitro)

Single / repeat dose

toxicity studies+

Bioanalysis / Toxicokinetics

Safety Pharmacology

Drug Metabolism

Lead candidateIdentified

Cli

nic

al

Non

-cli

nic

al

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

QUESTIONS???

THANK YOU !!