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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 !!