Drug Discovery & Development

Drug Discovery & Development

Introduction In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery. But now we know diseases are controlled at molecular and physiological level. Also shape of an molecule at atomic level is well understood. Information of Human Genome.

History of Drug Discovery :
Pre 1919 Herbal Drugs Serendiptious discoveries 1920s, 30s Vitamins Vaccines 1940s Antibiotic Era R&D Boost due to WW2 1950s New technology, Discovery of DNA 1960s Breakthrough in Etiology 1970s Rise of Biotechnology Use of IT 1980s Commercialization of Drug Discovery Combinatorial Chemistry 1990s Robotics Automation

Drug Design : Drug design may be defined as an effort to develop a new drug by molecular modification of lead compound for optimization of desired effects and minimization of side effects.

Lead Compound/Parent Compound :
A lead compound is a compound having a particular biological activity obtained either from natural or synthetic source. Example: Penicillin G, Prontosil.

Penicillin G : Penicillin G is a lead compound, obtained from natural source. It is not a ideal drug as- Acid unstable Narrow microbial spectrum. High allergenicity. Lower metabolic efficiency. Development of resistance. Lower oral absorption. Shorter plasma half life. Due to these above mentioned problems, Penicillin G is not used now. Penicillin G

Ampicillin: Molecular modification of Penicillin G to ampicillin reduces the problems with Penicillin G as it is- Acid stable Broad microbial spectrum. Less allergenicity. Greater metabolic efficiency. Ampicillin

Prontosil: Prontosil is a synthetic lead compound. It is metabolized in vivo to sulfanilamide from which various classes of drugs were further synthesized. Nitro reduction

Purpose of Drug design The purposes are:
To improve the selectivity of action To improve ADME Profile (Absorption, Distribution, Metabolism or Elimination) To obtain drug having most desirable properties than the lead compound in potency, toxicity and specificity. To obtain a marketable drug that can compete with an existing one. To reduce the cost of production. Exploitation of side effects of existing drug.

To Improve selectivity of action
The general structure of antihistamine (1st generation): Compound ED50 LD50 TR=LD50/ED50 Hetramine 0.51 260 500 Pyrilamine 0.0037 250 68,000 Chlorpheniramine (+) (-) 0.20 620 3100 19 450 24 To Improve selectivity of action To improve ADME Profile To obtain drugs having most desirable properties To obtain a marketable drug To reduce the cost of production To exploit the side effects of existing drug

To Improve ADME Profile (Absorption)
Eg. Progesterone: Orally inactive drug and breakdown in GIT. (orally active) Molecular Modification Progesterone (orally inactive) Prednisolone To Improve selectivity of action To improve ADME Profile To obtain drugs having most desirable properties To obtain a marketable drug To reduce the cost of production To exploit the side effects of existing drug

To Improve ADME Profile (Distribution)
Eg. Thiopental was developed from pentobarbital; by replacement of an oxygen atom by a sulphur atom. a Thiopental: Very fast onset & offset of action Very high lipid/water partition coefficient Rapidly across the blood brain barrier Persistence of drug in the body Pentobarbital (P.C.=0.05) Thiopental (P.C.=3.3) To Improve selectivity of action To improve ADME Profile To obtain drugs having most desirable properties To obtain a marketable drug To reduce the cost of production To exploit the side effects of existing drug

To Improve ADME Profile (Metabolism)
Eg. Development of procainamaide from procain. Procain: Active against certain cardiac arrhythmias. It is an ester & rapidly hydrolyzed by plasma & liver esterases. Local anesthetics. Procainamide: Duration of action is higher. The hydrolysis rate in vivo was greatly reduced. Same activity against cardiac arrhythmias. Procaine Procainamide To Improve selectivity of action To improve ADME Profile To obtain drugs having most desirable properties To obtain a marketable drug To reduce the cost of production To exploit the side effects of existing drug

To Obtain drugs having most desirable properties than the lead compound.
Mild antipyretic analgesic acetanilide is converted to aniline in vivo by deacetylation resulting in methemoglobinemia. Modification of acetanilide by hydroxylation in the para position yielded a compound that was not subjected to significant deacetylation & therefore was less toxic. Acetanilide Aniline Acetanilide Paracetamol To Improve selectivity of action To improve ADME Profile To obtain drugs having most desirable properties To obtain a marketable drug To reduce the cost of production To exploit the side effects of existing drug

To Obtain a marketable drug that can compete with an existing one.
To Improve selectivity of action To improve ADME Profile To obtain drugs having most desirable properties To obtain a marketable drug To reduce the cost of production To exploit the side effects of existing drug

To reduce the cost of production.
Diethylstilbestrol It is a synthetic drug Orally active compound Have estrogenic activity Estradiol Highly expensive drug To Improve selectivity of action To improve ADME Profile To obtain drugs having most desirable properties To obtain a marketable drug To reduce the cost of production To exploit the side effects of existing drug

To exploit the side effects of existing drug
An action seen as undesirable in one therapeutic context may become the primary drug action in another. Eg. Sulfonamide series were introduced as antibacterial agents. Exploitation of their side effects has lead to wholly new & useful drugs of 3 kinds: diuretic, antidiabetic and antithyroid drugs. To Improve selectivity of action To improve ADME Profile To obtain drugs having most desirable properties To obtain a marketable drug To reduce the cost of production To exploit the side effects of existing drug

Sources of Drugs: Ancient Source Modern Source Contribution of several source

Contribution of several Sources
Ancient Source Paracelsus ( ): ‘God indicated which medicinal agent would be adequate for treating a certain affected organ or the symptoms of a certain disease by best-owing a signal in the form of similarity, even if only spiritual, between the agent & the organ or symptoms.’ The ancient people thought that disease was caused by evil spirits or devils. They treated the patient with the substances of repugnant odor and appearance such like urine, feces, stinking plants or they restorted to nauseating fumigation. Ancient Source Modern Source Contribution of several Sources

Correlation with disease
Ancient Source Agent Correlation with disease Use Stalks of hepatica Resembling liver Liver disease Safron & Celandine Yellow color Jaundice Veronica flower Eye Eye Disease Veronica roots Intestinal worms Leaves of melissa Cordiform Heart disease Ancient Source Modern Source Contribution of several Sources

Modern Source Antibiotics Hormones Vaccine Chemical Synthesis Sera Ancient Source Modern Source Contribution of several Sources

Extraction Chromatography X-ray crystallography Synthesis Spectroscopy Ancient Source Modern Source Contribution of several Sources

Total 252 essential drugs are included in 1985 by Willo. 123 drugs Chemical synthesis 48.9% 28 drugs Vegetable parts 11.1% 24 drugs Partial chemical synthesis 9.5% 23 drugs Mineral Source 9.1% 22 drugs Extracted from animal organ 8.7% 16 drugs Microbial origin 6.4% 11 drugs Vaccine 4.3% 5 drugs Sera 2.0% Ancient Source Modern Source Contribution of several Sources

Cost & Place of Development of Drugs:
: 1165 new drugs were introduced in USA market. : 1787 new drugs in world market. Main Contributor: USA, Japan, UK, France, Italy, West Germany, Switzerland. Expanse: Cost ranges from $10 million to $100 million. Main Pharma Company: Hoechst-Roussel (Germany), RPR (France), Johnson & Johnson (USA), Sanofi (France), Sandoz (Switzerland), Bayer (Germany), Roche (Switzerland) etc. Last 30 years: 90% drugs from industry 9% drugs from University 1% drugs from Govt. Lab

Genesis of Drugs: Drugs find their way into therapeutics mainly by one of the following ways: Serendipity Random screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Serendipity Acetanilide & Phenyl butazone Antipyretics Penicillin
Valuable discoveries ‘accidentally’, ‘luckily’, ‘suddenly’ by pharmacists, chemists, physicians & other investigators is called serendipity. Examples: Acetanilide & Phenyl butazone Antipyretics Penicillin Antibacterial Piperazine Anthelmentic Chlorothiazide Diuretic Sulfonylureas Oral hypoglycemic Benzodiazepine Antianxiety agent Serendipity Random Screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Serendipity Acetanilide as Antipyretic:
A patient was infected with intestinal parasite and was supposed to be give Napthalene. But he was given accidentally “Acetanilide”. The fever of the patient was reduced. Thus acetanilide was accidentally discovered as an antipyretic agent. But now a day it is not used as antipyretic due to its nephro toxicity. Serendipity Random Screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Serendipity Penicillin as Antibacterials:
The antibacterial action was introduced accidentally by Flemming in 1920. When Flemming was working with a bacterial culture, the culture was contaminated with penicillium fungi. The penicillium fungi destroyed the cultured bacteria in the medium. In further stage, the active component ‘penicillin’ was isolated from the respective fungi. Serendipity Random Screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Serendipity Sulfonamide as Antithyroid Drug:
The antithyroid drugs of the thiouracil type had their origin in the accidental observation in 1941, that rats receiving ‘Sulfaguanidine’ developed goiters. The original purpose of the investigation was to study the role of intestinal bacteria in the biosynthesis of essential nutrients. Sulfaguanidine was being used to sterilize the gut. Serendipity Random Screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Serendipity Some Antithyroid Drugs: Thiourea Sulfaguanidine Thiouracil
(1st antithyroid drug) Sulfadiazine Serendipity Random Screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Serendipity Development of Thiouracil as Antithyroid Drug:
The systemic screening investigations found that Thiourea is a potent goitrogen. Sulfadiazine is most active. Since sulfadiazine contains a pyrimidine ring, it was logical to incorporate the thiourea moiety in a pyrimidine ring and thus thiouracil was obtained. This drug proved satisfactory for the clinical use in the treatment of hyperthyroidism. Thiouracil works by blocking thyroid hormone synthesis. Thus resulting in low circulating level of thyroid hormone. But thiouracil produced toxic reactions, mainly agranulocytosis (13% patients in a population of 2490 treated patients). Thiouracil (1st antithyroid drug) Serendipity Random Screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Serendipity Development of Thiouracil as Antithyroid Drug:
Modifications of the thiouracil structure was studied to find a safer drug and two safer drugs emerged: Propylthiouracil Methimazole Methimazole: Effective antithyroid drug. It is not a pyrimidine compound. Very low toxicity. Propylthiouracil: Effective antithyroid drug. Toxic reactions in only 3% patients when given in effective clinical dose. Propylthiouracil Methimazole Serendipity Random Screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Serendipity Selection or synthesis of soft drugs
Random Screening Extraction of active principles from natural sources Molecular modification of known drugs Selection or synthesis of soft drugs Drug latentiation Rational design of drugs

Drug Discovery & Development-Timeline
PRECLINICAL CLINICAL TRIALS FDA REVIEW 10,000 COMPOUNDS 250 COMPOUNDS 1 FDA APPROVED DRUG 5 COMPOUNDS ~6.5 YEARS ~7 YEARS ~1.5 YEARS

Drug Discovery Drugs Discovery methods: Random Screening
Molecular Manipulation Molecular Designing Drug Metabolites Serendipity

Clinical Trials and Therapeutics
Target Selection Cellular and Genetic Targets Genomics Proteomics Bioinformatics Lead Discovery Synthesis and Isolation Combinatorial Chemistry Assay development High-Throughput Screening Medicinal Chemistry Library Development SAR Studies In Silico Screening Chemical Synthesis In Vitro Studies Drug Affinity and Selectivity Cell Disease Models MOA Lead Candidate Refinement In Vivo Studies Animal models of Disease States Behavioural Studies Functional Imaging Ex-Vivo Studies Clinical Trials and Therapeutics

Cellular & Genetic Targets
Target Selection Target selection in drug discovery is defined as the decision to focus on finding an agent with a particular biological action that is anticipated to have therapeutic utility — is influenced by a complex balance of scientific, medical and strategic considerations. Target identification: to identify molecular targets that are involved in disease progression. Target validation: to prove that manipulating the molecular target can provide therapeutic benefit for patients. Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Target Selection Biochemical Classes of Drug Targets G-protein coupled receptors - 45% enzymes - 28% hormones and factors - 11% ion channels - 5% nuclear receptors - 2% Techniques for Target Identification Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Cellular & Genetic Targets:
Involves the identification of the function of a potential therapeutic drug target and its role in the disease process. For small-molecule drugs, this step in the process involves identification of the target receptors or enzymes whereas for some biologic approaches the focus is at the gene or transcription level. Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease. Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Cellular & Genetic Targets:
Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease. Compounds are then identified that have various interactions with the drug targets that might be helpful in treatment of a specific disease. Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Genomics: The study of genes and their function. Genomics aims to understand the structure of the genome, including the mapping genes and sequencing the DNA. Seeks to exploit the findings from the sequencing of the human and other genomes to find new drug targets. Human Genome consists of a sequence of around 3 billion nucleotides (the A C G T bases) which in turn probably encode 35,000 – 50,000 genes. Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Genomics: Drew’s estimates that the number of genes implicated in disease, both those due to defects in single genes and those arising from combinations of genes, is about 1,000 Based on 5 or 10 linked proteins per gene, he proposes that the number of potential drug targets may lie between 5,000 and 10,000. Single Nucleotide Polymorphism (SNP) libraries: are used to compare the genomes from both healthy and sick people and to identify where their genomes vary. Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Proteomics: It is the study of the proteome, the complete set of proteins produced by a species, using the technologies of large – scale protein separation and identification. It is becoming increasingly evident that the complexity of biological systems lies at the level of the proteins, and that genomics alone will not suffice to understand these systems. It is also at the protein level that disease processes become manifest, and at which most (91%) drugs act. Therefore, the analysis of proteins (including protein-protein, protein-nucleic acid, and protein ligand interactions) will be utmost importance to target discovery. Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Proteomics: Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems. Target identification with proteomics is performed by comparing the protein expression levels in normal and diseased tissues. 2D PAGE is used to separate the proteins, which are subsequently identified and fully characterized with LC-MS/MS. Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Bioinformatics: Bioinformatics is a branch of molecular biology that involves extensive analysis of biological data using computers, for the purpose of enhancing biological research. It plays a key role in various stages of the drug discovery process including target identification computer screening of chemical compounds and pharmacogenomics Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Bioinformatics: Bioinformatics methods are used to transform the raw sequence into meaningful information (eg. genes and their encoded proteins) and to compare whole genomes (disease vs. not). Can compare the entire genome of pathogenic and non-pathogenic strains of a microbe and identify genes/proteins associated with pathogenism Using gene expression micro arrays and gene chip technologies, a single device can be used to evaluate and compare the expression of up to genes of healthy and diseased individuals at once Cellular & Genetic Targets Genomics Proteomics Bioinformatics Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Lead Discovery: Identification of small molecule modulators of protein function The process of transforming these into high-content lead series. Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Synthesis and Isolation:
Separation of mixture Separation of impurities In vitro chemical synthesis Biosynthetic intermediate Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Combinatorial Chemistry:
Rapid synthesis of or computer simulation of large no. of different but structurally related molecules Search new leads Optimization of target affinity & selectivity. ADME properties Reduce toxicity and eliminate side effects Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Assay Development Used for measuring the activity of a drug.
Discriminate between compounds. Evaluate: Expressed protein targets. Enzyme/ substrate interactions. Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

High throughput screening:
Screening of drug target against selection of chemicals. Identification of highly target specific compounds. Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

High throughput screening:
Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Medicinal Chemistry: It’s a discipline at the intersection of synthetic organic chemistry and parmacology. Focuses on small organic molecules (and not on biologics and inorganic compounds) Used in Drug discovery (hits) Lead optimization (hit to lead) Process chemistry and development Library Development SAR Studies In Silico Screening Chemical Synthesis Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Library Development: Collection of stored chemicals along with associated database. Assists in High Throughput Screening Helps in screening of drug target (hit) Based on organic chemistry Library Development SAR Studies In Silico Screening Chemical Synthesis Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

SAR Studies: Helps identify pharmacophore
The pharmacophore is the precise section of the molecule that is responsible for biological activity Enables to prepare more active compound Allow elimination of excessive functionality Library Development SAR Studies In Silico Screening Chemical Synthesis Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

SAR Studies: Morphine Molecule Library Development SAR Studies
In Silico Screening Chemical Synthesis Morphine Molecule Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

In silico screening: Computer simulated screening of chemicals
Helps in finding structures that are most likely to bind to drug target. Filter enormous Chemical space Economic than HTS Library Development SAR Studies In Silico Screening Chemical Synthesis Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Chemical Synthesis: Involve production of lead compound in suitable quantity and quality to allow large scale animal and eventual, extensive human clinical trials Optimization of chemical route for bulk industrial production. Suitable drug formulation Library Development SAR Studies In Silico Screening Chemical Synthesis Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

In Vitro Studies: (In glass) studies using component of organism i.e. test tube experiments Examples- Cells derived from multicellular organisms Subcellular components (Ribosomes, mitochondria) Cellular/ subcellular extracts (wheat germ, reticulocyte extract) Purified molecules (DNA,RNA) Drug Affinity and Selectivity Cell Disease Models MOA Lead Candidate Refinement Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

In Vitro Studies: Advantages:
Studies can be completed in short period of time. Reduces risk in post clinical trials permits an enormous level of simplification of the system investigator can focus on a small number of components Drug Affinity and Selectivity Cell Disease Models MOA Lead Candidate Refinement Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Drug affinity and selectivity
Drug affinity is the ability of drug to bind to its biological target (receptor, enzyme, transport system, etc.) Selectivity- Drug should bind to specific receptor site on the cell (eg. Aspirin) Drug Affinity and Selectivity Cell Disease Models MOA Lead Candidate Refinement Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Cell disease models Isogenic human disease models- are a family of cells that are selected or engineered to accurately model the genetics of a specific patient population, in vitro Stem cell disease models-Adult or embryonic stem cells carrying or induced to carry defective genes can be investigated in vitro to understand latent molecular mechanisms and disease characteristics Drug Affinity and Selectivity Cell Disease Models MOA Lead Candidate Refinement Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Lead Candidate refinement
Optimizing chemical hits for clinical trial is commonly referred to as lead optimization The refinement in structure is necessary in order to improve Potency Oral Availability Selectivity pharmacokinetic properties safety (ADME properties) Drug Affinity and Selectivity Cell Disease Models MOA Lead Candidate Refinement Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Animal models of Disease States
In vivo studies Its experimentation using a whole, living organism. Gives information about, Metabolic profile Toxicology Drug interaction Animal models of Disease States Behavioural Studies Functional Imaging Ex-Vivo Studies Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Animal models of disease states
Test conditions involving induced disease or injury similar to human conditions. Must be equivalent in mechanism of cause. Can predict human toxicity in 71% of the cases. Eg. SCID mice-HIV NOD mice- Diabetes Danio rerio- Gene function Animal models of Disease States Behavioural Studies Functional Imaging Ex-Vivo Studies Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Behavioural Studies Tools to investigate behavioural results of drugs. Used to observe depression and mental disorders. However self esteem and suicidality are hard to induce. Example: Despair based- Forced swimming/ Tail suspension Reward based Anxiety Based Animal models of Disease States Behavioural Studies Functional Imaging Ex-Vivo Studies Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Functional Imaging: Method of detecting or measuring changes in metabolism, blood flow, regional chemical composition, and absorption. Tracers or probes used. Modalities Used- MRI CT-Scan Animal models of Disease States Behavioural Studies Functional Imaging Ex-Vivo Studies Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Ex-Vivo Studies: Experimentation on tissue in an artificial environment outside the organism with the minimum alteration of natural conditions. Counters ethical issues. Examples: Measurement of tissue properties Realistic models for surgery Animal models of Disease States Behavioural Studies Functional Imaging Ex-Vivo Studies Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Clinical trials: Set of procedures in medical research and drug development to study the safety and efficacy of new drug. Essential to get marketing approval from regulatory authorities. May require upto 7 years. Phase-I Phase-II Phase-III Phase-IV Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Phase 0: Recent designation, also known as human micro-dosing studies. First in human trials, conducted to study exploratory investigational new drug. Designed to to speed up the development of promising drugs. Concerned with- Preliminary data on the drug’s pharmacodynamics and pharmacokinetics Efficacy of pre-clinical studies. Phase-I Phase-II Phase-III Phase-IV Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Phase I: Clinical Pharmacologic Evaluation
First stage of testing in human subjects. 20-50 Healthy Volunteers Concerned With: Human Toxicity. Tolerated Dosage Range Pharma-cology/dynamics Phase-I Phase-II Phase-III Phase-IV Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Phase I: Types of Phase-I Trials SAD (Single Ascending Dose)
MAD (Multiple Ascending Dose) Food effect Phase-I Phase-II Phase-III Phase-IV Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Phase II: Controlled Clinical Evaluation. 50-300 Patients
Controlled Single Blind Technique Concerned With: Safety Efficacy Drug Toxicity Drug Interaction Phase-I Phase-II Phase-III Phase-IV Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Phase III: Extended Clinical Trials. Most expensive & time consuming.
Patients. Controlled Double Blind Technique. Concerned With: Safety, Efficacy Comparison with other Drugs Package Insert Phase-I Phase-II Phase-III Phase-IV Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Phase IV: Post Marketing Surveillance.
Designed to detect any rare or long-term adverse effects. Adverse Drug Reaction Monitoring. Pharmacovigilance. Phase-I Phase-II Phase-III Phase-IV Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies In Vivo Studies Clinical Trials

Drug Discovery & Development-Timeline
PRECLINICAL CLINICAL TRIALS FDA REVIEW 10,000 COMPOUNDS 250 COMPOUNDS 1 FDA APPROVED DRUG 5 COMPOUNDS ~6.5 YEARS ~7 YEARS ~1.5 YEARS

Drug Discovery & Development

Similar presentations

Presentation on theme: "Drug Discovery & Development"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Drug Discovery & Development

Similar presentations

Presentation on theme: "Drug Discovery & Development"— Presentation transcript:

Similar presentations

About project

Feedback