drug discovery and development by vinay gupta

April 11, 2023 vinay-pharmacology 1

Clinical Presentation at

UP RIMS & R, Saifai, EtawahOn

23rd June 2011

Vinay Gupta(Lecturer)

Department of PharmacologyUP RIMS & R

Drug Discovery & Development


Drug Discovery & Development Process

Ref: Bennett & Brown: clinical pharmacology

Clinical StudyClinical StudyClinical StudyClinical StudyClinical StudyClinical Study


Clinical Development of Drug

Clinical trials in the different countries are approved & monitored by different regulatory agencies-

1) In India- DCGI (Drug Controller General of India) Under CDSCO (Central Drug Standard Control

Organization).

2) In UK- MHRA (Medicine & Healthcare Products Regulatory Agency), advised by CSM (Committee on Safety of Medicine).

3) In USA- FDA (Food & Drug Administration) & CDER (Center for Drug Evaluation & Research).


Techniques of Drug Discovery

Older Approaches-

Natural Products (Phytochemical & Pharmacological Evaluation)-

Traditional Medicines-

Modification of the Structure of known drugs-

New uses of drug already in general use-


Natural Product Screening-

PHARMACOLOGICALBIOLOGICALSCREENING

Extracts

Purify

Rejected

Positive

Negative

Establish StructureTo Serve as

Lead Compound


Pri-clinical Studies Discovery & Development Cycle

Establishment of Test in Animals

LEAD COMPOUND DESIRED ACTIVITY

CrudeExtract

Comp.Of

KnownStructure

TargetedDisease

ofInterest

In vitroActivity

In vivoActivity

ClinicalActivity

Purification&

Characterisation

Establishment of Target Organ

Establishment of Molecular Target


Newer Approaches-

Molecular Modeling-

Biotechnology & Recombinant DNA Technology-

Positron Emission Tomography (PET)-

Combinatorial Chemistry-

Techniques of Drug Discovery


Combinatorial Chemistry- The objective of combinatorial chemistry is the generation of huge

numbers of compounds very quickly.THERAPEUTIC TARGET

LEAD DISCOVERY

LEAD OPTIMIZATION

DEVELOPMENT CANDIDATE

DRUG

CombinatorialChemistryImpacts Here


Approaches to Drug discovery

Target Selection-

Molecular Targets (genetic information ).

Selection Of Lead Compound.

Validation of Lead Compound.


Many targets are most often Proteins, but Nucleic Acids may also be an attractive target.

TARGET MECHANISM

Enzyme Inhibitor- reversible or irreversible

Receptor agonist or antagonist Nucleic acid binder, modifier (alkylating agent)

or substrate Ion channels blockers or openers Transporters uptake inhibitors


Pre-clinical Studies in Animals

At the Pre-clinical stage, the regulatory bodies generally ask about-

PharmacologicalTesting

To determine the Acute Toxicity of the drug in

at least two species of animals.

To develop a Pharmacological profile of Drug.

ToxicologicalTesting

To conduct Pharmacokinetic studies from 2

weeks to 3 months.Pharmacokinetic

Testing

PharmacologicalTesting

To develop a Pharmacological profile of Drug. PharmacologicalTesting

To develop a Pharmacological profile of Drug.

ToxicologicalTesting

To conduct Pharmacokinetic studies from 2

weeks to 3 months.Pharmacokinetic

Testing


Pharmacological Testing-

Animal Model of Human Disease May Occur- 1) Naturally- eg. squirrel monkeys develop dementia in

old age which is behaviorally & histologically similar to AD (Alzheimer's Disease) in human with about same pathophysiology.

2) By introduction of genetic defect into the germ cells of an animal strain so that its reproduction produces offspring with the disease of interest.

3) Using drugs/ chemicals to alter or produce disease of Interest in animal model.

Pre-clinical Studies in Animals…


Toxicological Studies-

Toxicity studies are done to calculate-

1) Maximum Tolerated Dose. (MTD)

2) Gross Pathology to Indicate Target Disease.

3) Satisfactory Therapeutic Ratio ( Efficacy & Toxicity).



Toxicity studies Required for Complete Pre-clinical development-

Acute Toxicity 2 weeks studies in 3-4 species to determine maximum tolerated dose (MTD).

Sub-Acute Toxicity 6 month studies in 2 species.

Chronic Toxicity Up to 12 month studies in rodents & non-rodent to determine if adverse effects occur with repeated daily dosing.Oncology studies for at least 18 months in mice & for 24 months in rat.

Reproductive Up to 9 month studies in 2 species to determine effects of drug on fertility & reproduction & expose any teratogenic effects.



‘First do no harm

It is good remedy some times to use nothing.’

Hippocrates (460-355 BC)


‘That medicine is a right one and pure one which cures a disease

–physical, mental, spiritual- and does not give rise to

adverse reactions and does not create other disease.’

Charak Samhita


‘All things are poisons and there is nothing that is harmless,

the dose alone

decides that something is not poison.’

Paracelsus(1493-1541)


Pharmacokinetic Testing Physio-chemical properties. Designing Dosage forms.

Product Stability Shelf life. Drug Expiry.

Pre-clinical Studies…


Investigational New Drug Application (INDA)

IND application is a result of a successful pre-clinical development program & with this a researcher advances to the clinical trials with following results & information-

1) Animal Pharmacological & Toxicological studies with an assessment that the product is reasonably safe for initial testing in human beings.

2) Information pertaining to the composition, stability & control use for manufacturing the drug substances. This information is assessed to ensure that the manufacturing company can adequately produce & supply consistent batches of drug.


INDA Cont…

3) Detailed protocols of proposed clinical studies to assess whether the initial phase trials will expose subject to unnecessary risks & details of Clinical investigators (usually Physicians/concerned branch Specialist) who oversee the administration & monitoring of the subject for experimental compound.

The IND is not an application for marketing approval but it is an approval for further proceedings of clinical trials in human beings.


Phases of Clinical Development

Phase I: Human Pharmacology (20 to 50 subjects)

Healthy volunteers or volunteer patients according to class of drug & its safety & initial introduction of experimental drug to humans.

Deals with pharmacokinetics (ADME) &

Pharmacodynamics with tolerability, safety & efficacy parameters.

Time Period: 1-2 Years


Phase 1 Trial Address: How rapidly the drug is absorbed. Where is the drug distributed in the body. Which organ/system are involved in metabolism of the drug. Drug elimination rate in the body.

Phase 1 Trial Address: How rapidly the drug is absorbed. Where is the drug distributed in the body. Which organ/system are involved in metabolism of the drug. Drug elimination rate in the body.

Phase I Trial Address: How rapidly the drug is absorbed. Where is the drug distributed in the body. Which organ/system are involved in metabolism of the drug. Drug elimination rate in the body.


Phase II: Therapeutic Exploration (50 to 300 subjects) Volunteer patients. The study helps to determine common short term side effects &

risks associated with the experimental drug. Establishment of Pharmacokinetic & Pharmacodynamics Dose

ranging, in carefully controlled studies for efficacy & safety. The study may be conducted with test & placebo drugs as-

• Open non blind trial.

• Single blind trial.

• Double blind trial.



Phase II Trial Address: What is the minimum effective dose ? What is the max. tolerated effective dose ? Is the drug effective in mild, moderate & severe case of disease/condition. Is the drug effective for all expected indications.


Phase III: Therapeutic Confirmation (250 to 1,000+)

Phase 3 studies are expanded as controlled & uncontrolled trials. The aim of this phase is to verify the drug’s effectiveness & possibility of

any adverse reaction in a large group of patients over a longer period of exposure, to establish safety & efficacy of experimental drug & comparison with existing drug.

In b/w all Phases, the regulatory bodies can impose a clinical hold if the study is unsafe or if the protocol design is deficient in meeting its stated objectives.

Once the phase 3 clinical trial has been completed satisfactorily, the organization can apply for marketing application to the regulatory authorities to market the drug by filing NDA (takes 12 months for approval).



The value of toxicity testing is illustrated by experience with triparanol a cholesterol lowering drug marketed in the USA in 1959.

Three years later a team from FDA made a surprise visit that revealed falsification of toxicological data, demonstrating cataracts in rats & dogs, the drug was withdrawn but some patients who had been taking it for a year or more also developed cataract.


Phase III Trial Address: Overall Risk-benefit relationship. Adverse Reactions in large group of patients over a longer period of exposure . The ideal dosage regimen.Should the drug is allowed to be marketed.


New Drug Application (NDA)

It is an application submitted to regulatory agency (DCGI) for permission to market a new drug product.

The sponsor have to submit the pre-clinical & clinical test data, analysis, drug information & description of manufacturing procedure.

After a NDA is received, it undergoes a technical screening generally referred as Completeness review for a period of 12 months.

After approval, the license is issued to the sponsor for the exclusive marketing rights for a limited period which is further renewable with satisfactory drug response.


Phase 4 (Post Marketing Surveillance)

Some times ADR only come to light after drug has been in the market for a while & has been used by a large population. Post Marketing Surveillance identifies such problems.

Withdrawal of a drug from the market is not an uncommon occurrences eg.

Drug Name Withdrawn Remarks

Thalidomide 1950-60 Teratogenicity (Phocomelia).

Phenacetin 1983 Risk of cancer & Kidney Problems

Chlormezanone 1996 Toxic epidermal necrolysis

Cisapride 2000 Risk of Cardiac Arrhythmias

Roficoxib 2004 Risk of MI

Tegaserod 2007 Imbalance of cardiovascular ischemic events

Sibutramine 2010 Europe, US & Australia (Cardiovascular Risk)


Surveillance System: Pharmacovigilance

The term Pharmacovigilance refers to the process of identifying & responding to issues of drug safety through detection in the community of adverse drug effects.

ADR monitoring in India: Central Drugs Standard Control Organization( CDSCO) under ministry of health and family welfare launched the National Pharmacovigilance Programme (NPP) in Nov.2004.

Under this programme, the whole country is divided into zones and regions for operational efficiency.

The reports from periphery is sent to higher centre and then to WHO center (Uppsala Medical Centre, Sweden).


CDSCO (Central Drug Standard Control Organization), Nirman Bhawan, New Delhi is at the top of the hierarchy followed by two zonal centers viz. Seth GS Med. College, Mumbai and AIIMS, New Delhi.

Five regional pharmacovigilance centers are-

Kolkata (IPGMR-SSKM Hospital) Mumbai (TN Med.College)Nagpur (Indira Gandhi Med.College)New Delhi (Lady Hardinge Med.College)Pondicherry (JIPMER)

ADR monitoring in India:


A Tale to RememberThe Thalidomide Disaster

Seal Extremities

Phocomelia

CONTERGAN


Research & Development Time Scale

Pre-Clinical

(Synthesis)

IND Clinical

Study

NDA Phase IV

(Launch)

Patent

Expiry

1992 1996 2002 2003 2004(10-12 year)

2012

Discovery

Research

Clinical Development Regulatory

Review

Development &

Post Marketing

2000-6000 compounds 1 Drug

RATE OF ATTRITION

Cost about 500 million Dollar


Essential Clinical Trial Documentation

1) Protocol- A document that states Objectives, Design, Methodology & Statistical consideration of study.

2) Informed Consent Document (ICD)- A document for voluntary written consent of a subject’s willingness to participate in the particular study.

3) Investigator’s Brochure (IB)- A collection of data including justification for the proposed study, the nature, scale & duration of the proposed trial & to evaluate the potential safety.

4) Case/Clinical Record Form (CRF)- Recorded data & other information on each trial subject on a prescribed format.


5) Source Document (SD)- may include Subject’s file, recordings from automated instruments, tracings, X ray & other investigational documents.

6) Regulatory Approval- a document to grant permission to conduct a trial from Investigator’s site. The approval must be obtained prior to initiating the clinical trial & the duration of approval.

7) ERB/IRB/IEC Approval- The approval must be obtained prior to initiating any clinical trial & the duration of approval.

8) Financial Agreement- Financial aspect of the trial b/w investigator (institute) & the sponsor.



9) Curriculum Vitae (CV)- A document to provide qualification & eligibility of investigator(s) prior to initiate the trial.

10) Investigational Product Accountability- A document to provide complete accountability of investigational product including receipt, dispensing & storage condition of the test drug etc.

11) Certificates of Analysis (COA)- A document to provide identity, purity & strength in term of assay of investigational product.

12) Clinical Study Report (CSR)- A report prepared at the end of the trial including results & interpretation for submission to regulatory bodies.



Statistical Approaches In Clinical Trials

Requirement of Statistics-

“Making wise decision in the face of uncertainty.”

To find the action of a drug – the response produced is due to the drug or independent of it.

To compare the safety & efficacy of a particular drug or two different drugs.

To find out the relative potency of a new drug with respect to the standard drug.

To find out an association between two attributes.

Clinical trial design based on the primary & secondary objectives.


Power and sample size.Bias & Confounding.Randomization.Stratification.Blinding.Intent-to-Treat.Randomized controlled designs-

Parallel Design Multi arm parallel Design Factorial Design Cross-over Design

Two stage Design Adaptive Design Equivalence Design & non inferiority Design



Statistical Errors in Clinical Trials Type 1 Error Type 2 Error

Statistical Analysis Methods-

1) Parametric Tests ANOVA t-Test One Sample t-Test Two Sample t-Test Paired t-Test

2) Non Parametric Tests Mann-Whitney U Test Wilcox on Test Krushall-Wallis Test Friedman’s Test



Drug Regulatory Act & Schedules

Schedule C - biological & other special products eg. Vaccines, Insulin, Sera & Antibiotics.

Schedule F - Specification of standard Ophthalmic preparations.

Schedule G - with a label that states “caution” dangerous to use except under medical supervision.

Schedule H- Prescription Drug.

Schedule J- HIV & Atherosclerosis.

Schedule X- drugs having dependence liability, the supply of these drugs has to be maintained & recorded in a register.

Schedule Y- Clinical trials in India.Schedule W- drugs marketed under Generic names.


Ethical Review Board (ERB)

ERB is also known as- IRB - Institutional Review Board. IEC - Independent Ethics Committee. EC - Ethics Committee.

Composition of ERB- (As per ICMR-2000 & Indian GCP-2001) Minimum of 5 Memb. (max. up to 15) Includes 1 non-scientific memb. Includes 1 memb. Independent from Institute/ trial site. 1 legal expert. Rest may be clinicians & scientists.


CPCSEA (Committee for the Purpose of Control & Supervision of Experiments on Animals)

Provisions of the prevention of the cruelty to animals Act,1960 & the rules under the Act of 1998 & 2001.The concerned research institute are required to get themselves registered with CPCSEA before commencing the research.The main activities are- Registration of institute for breeding of animals. Registration of establishment for experiments on animals. Approval of animal house facilities. Permission of committee (IAEC) for conducting experiments.

IAEC Composition- 1 Veterinarian, a non-scientific socially aware member, a representative of CPCSEA, Scientist in-charge of animals facility of the institute & other scientist.


Indian Patent Office & Duration

Patent Duration : Term of every patent in India is 20 years from the date of filling of patent application, irrespective of whether it is filled with provisional or complete specification.

Administrated by the office of the CGPDTM (Controller General of Patents, Design & Trade Marks) Mumbai.

Headquarter – Kolkata Branch Office – 1) New Delhi

2) Mumbai & 3) Chennai.


DISEASE WISE CLINICAL TRIALS DONE IN INDIA


CDSCOOverall Global Clinical Trials India 3rd most preferred destination

Notes: Higher scores indicate higher levels of attractiveness. The 15 countries analyzed were selected based on size, diversity & geographical distribution.

Czec. Rep. U.K.

China

Russia

Brazil

ArgentinaPoland

HungaryGermany

TaiwanIsrael

SingaporeIreland

South Africa

6.10

5.585.55

5.265.005.00

4.904.84

4.814.69

4.46

4.284.27

3.86

4.56

United USA 6.88

Patient pool Cost efficiency Regulatoryconditions

Relevantexpertise

Infrastructure &environment

Scale : 1-10

INDIA


Study Average US cost (in millions)

Indian cost

Phase I 40 50% less than the average cost in US

Phase II 100 60%less than the average cost in US

Phase III 160 60%less than the average cost in US

Cost of Clinical trials in USA / India


Growth of Indian Clinical Trial Industry in India

Growth of Indian Clinical Trial Industry

35120 160

300

1000

0

200

400

600

800

1000

1200

2002 - 03 2005 - 06 2006 - 07 2007 - 08 2009 - 2010

Year

US

D (

Mill

ion

)

As per FICCI - Ernst & Young Survey Report, India can attract between 5 - 10% of the global contract research outsourced market . (all services including chemistry, toxicology and clinical research) over

next 5 years.


Clinical Trials from India(www.clinicaltrials.gov)

1

10

100

1000

10000

100000

Phase of trial

No

. T

rial

s (L

og

tra

nsf

orm

ed)

India 32 165 394 63

USA 6324 11305 5683 2474

All 8540 16878 11662 6142

Phase-1 Phase-2 Phase-3 Phase-4


Country All Studies % Industry Sponsored

Australia 1572 62.72

Chinese Taipei 903 45.29Japan 732 67.76

Korea 674 72.26

China 643 53.50

India 582 72.16

Singapore 335 68.36

Thailand 327 69.42

Chinese Hong Kong 250 82.00

Philippines 206 93.20

Malaysia 180 93.33

CLINICAL TRIAL ACTIVITIES IN ASIA ALL STUDIES

www.clinicaltrials.gov-Snapshot: 7 Feb 2008 Countries with more than 100 studies listed


Sr. No. Company Clinical Trial in India CLINICAL Trial in China

1 Astra Zeneca 10 10

2 BMS 17 6

3 Eli Lilly 17 12

4 GSK 22 14

5 J&J 20 13

6 Merck 8 5

7 Novartis 9 6

8 Pfizer 16 5

9 Roche 5 14

10 Sanofi Aventis 15 13

Total 139 98

GLOBAL CLINICAL TRIALS COMPARISON INDIA : CHINA


INDIA BUILDING A TRACK RECORD

Clinical Trial Data From India to Achieve an FDA NDA

Drug Company Compound Researched Indication US Launch

Canagene Hepagam Hepatitis B Jan 06Eli Lilly Alimta Cancer Feb-04Eli Lilly Cialis Erectile dysfunction Nov-3Jannsen Risperidal Psychosis Oct-03Wyeth Flumist Influenza May-03Alcon Vigamox Ophthalmic Infections Jan-03Glaxo Lamictal Epilepsy Jan-03Novrtis Zelcorm Irritable Bowel Syndrome Jul-02Pfizer Vfend Fungal Infection May-02Eli Lilly Xigris Septicemia Nov-01Santen Quixin Ophthalmic Infections Oct-00


Evolution of Drug Regulation

1) Virus Toxin Act of 1902.2) Federal Food & Drugs Act of 1906.3) The Sherley Amendment of 1912.4) The Food, Drug & Cosmetic Act of 1938.5) The Federal Insecticide, Fungicide & Rodenticide Act of 1947.6) The Durham Humphery Amendment of 1951.7) Insulin & Antibiotic Certification Amendments 1952.8) Comprehensive Drug Abuse Prevention & Control Act of 1970.9) Orphan Drug Act of 1983.10) Drug Price Competition & Patent Term Restoration Act 1984.11) Generic Drug Act of 1990.12) FDA Modernizations Act of 1997.13) Paediatric Exclusively Act of 1998.14) Prescription Drug User Fee Act of 1994-2003.

THANKS

Dedicated to those poor animals whose

life were sacrificed for our

future


INDIA BUILDING A TRACK RECORD

Clinical Trial Data From India to Achieve an FDA NDA

Drug Company Compound Researched Indication Launch

Canagene Hepagam Hepatitis B Jan 06Eli Lilly Alimta Cancer Feb-04Eli Lilly Cialis Erectile dysfunction Nov-3Jannsen Risperidal Psychosis Oct-03Wyeth Flumist Influenza May-03Alcon Vigamox Ophthalmic Infections Jan-03Glaxo Lamictal Epilepsy Jan-03Novrtis Zelcorm Irritable Bowel Syndrome Jul-02Pfizer Vfend Fungal Infection May-02Eli Lilly Xigris Septicemia Nov-01Santen Quixin Ophthalmic Infections Oct-00


Ethical Review Board (ERB)

ERB is also known as- IRB - Institutional Review Board. IEC - Independent Ethics Committee. EC - Ethics Committee.

Composition of ERB- (As per ICMR-2000 & Indian GCP-2001) Minimum of 5 Memb. (max. up to 15) Includes 1 non-scientific memb. Includes 1 memb. Independent from Institute/ trial site. 1 legal expert. Rest may be clinicians & scientists.


CPCSEA (Committee for the Purpose of Control & Supervision of Experiments on Animals)

Provisions of the prevention of the cruelty to animals Act,1960 & the rules under the Act of 1998 & 2001.The concerned research institute are required to get themselves registered with CPCSEA before commencing the research.The main activities are- Registration of institute for breeding of animals. Registration of establishment for experiments on animals. Approval of animal house facilities. Permission of committee (IAEC) for conducting experiments.

IAEC Composition- 1 Veterinarian, a non-scientific socially aware member, a representative of CPCSEA, Scientist in-charge of animals facility of the institute & other scientist.


Indian Patent Office & Duration

Patent Duration : Term of every patent in India is 20 years from the date of filling of patent application, irrespective of whether it is filled with provisional or complete specification.

Administrated by the office of the CGPDTM (Controller General of Patents, Design & Trade Marks) Mumbai.

Headquarter – Kolkata Branch Office – 1) New Delhi

2) Mumbai & 3) Chennai.


Drug Regulatory Act & Schedules

Schedule C - biological & other special products eg. Vaccines, Insulin, Sera & Antibiotics.

Schedule F - Specification of standard Ophthalmic preparations.

Schedule G - with a label that states “caution” dangerous to use except under medical supervision.

Schedule H- Prescription Drug.

Schedule J- HIV & Atherosclerosis.

Schedule X- drugs having dependence liability, the supply of these drugs has to be maintained & recorded in a register.

Schedule Y- Clinical trials in India.Schedule W- drugs marketed under Generic names.


Important Results in Drug ResearchSince 1806 & onwards

1806

1875

1884

1888

1899

1903

1909

1921

1922

1928

1928

1935

1944

1945

1952

1956

1960

Morphine

Salicylic acid

Cocaine

Phenacetin

Acetylsalicylic acid

Barbiturates

Arsphenamine

Procaine

Insulin

Estrone

Penicillin

Sulphachrysoidine

Streptomycin

Chloroquine

Chlorpromazine

Tolbutamide

Chlordiazepoxide

Hypnotic

Antiinflammatory

Stimulant, local anesthetic

Analgesic and antipyretic

Analgesic and antipyretic

Sedatives

Antisyphilitic

Local anesthetic

Antidiabetic

Female sex hormone

Antibiotic

Bacteriostatics

Antibiotics

Antimalarials

Neuroleptic agent

Oral antidiabetics

Tranquillizer

1962

1963

1964

1971

1975

1976

1981

1981

1983

1984

1985

1986

1987

1987

1988

1990

1991

1993

Verapamil

Propranolol

Furosemide

L-Dopa

Nifedipine

Cimetidine

Captopril

Ranitidine

Cyclosporin A

Enalapril

Mefloquine

Fluoxetine

Artemisinin

Lovastatin

Omeprazole

Ondansetron

Sumatriptan

Risperidon

Calcium channel blocker

Antihypertensive agent (beta-blocker)

Diuretic agent

Anti-Parkinson agent

Calcium channel blocker

Anti-ulcus agent (H2 blocker)

Antihypertensive (ACE inhibitor)

Anti-ulcus agent (H2 blocker)

Immunosuppressant

Antihypertensive (ACE inhibitor)

Antimalaria agent

Antidepressant (5-HT transporter)

Antimalaria agent

Cholesterol biosynthesis inhibitor

Anti-ulcus agent

Antiemetic agent (5-HT3 blocker)

Anti-migraine agent (5-HT1 blocker)

Antipsychotic agent


1994

1995

1995

1996

1996

1996

1997

1997

1997

1998

1998

1999

1999

1999

2001

2001

Famciclovir

Losartan

Dorzolamide

Meloxicam

Nevirapin

Indinavir, Ritonavir,

Saquinavir

Nelfinavir

Finasteride

Sibutramine

Orlistat

Sildenafil

Celecoxib, Rofecoxib

Amprenavir

Zanamivir, Oseltamivir

Fondaparinux

Imatinib

Anti-herpes (DNA polymerase inhibitor)

Antihypertensive agent (A II antagonist)

Glaucoma (Carbonic anhydrase inhib.)

Anti-arthritis agent (COX 2 inhibitor)

HIV reverse transcriptase inhibitor

HIV protease inhibitors

HIV protease inhibitor

Hair loss

Adipositas (uptake blocker)

Adipositas (lipase inhibitor)

Erectile dysfunction (PDE inhibition)

Anti-arthritis agents (COX-2 inhibitors)

HIV protease inhibitor

Influenza (neuraminidase inhibitors)

Thrombosis (synthetic LMWH)

CML (specific abl-TK inhibitor)

drug discovery and development by vinay gupta

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