Modern Day Drug Discovery and Development PDF

# MODERN DAY DRUG ## DRUG DEVELOPMENT CAN BE CLASSIFIED INTO 3 STAGES 1. **Stage 1 - Drug Discovery:** During which candidate molecules are chosen on the basis of their pharmacological properties. 2. **Stage 2 - Preclinical Development:** During which a wide range of non-human studies (e.g. toxici...

# MODERN DAY DRUG ## DRUG DEVELOPMENT CAN BE CLASSIFIED INTO 3 STAGES 1. **Stage 1 - Drug Discovery:** During which candidate molecules are chosen on the basis of their pharmacological properties. 2. **Stage 2 - Preclinical Development:** During which a wide range of non-human studies (e.g. toxicity testing, pharmacokinetic/pharmacodynamic analysis and formulation) are performed. 3. **Stage 3 - Clinical Development:** During which the selected compound is tested for efficacy, side effects and potential dangers in volunteers and patients. 4. Regulatory approval ## DRUG DEVELOPMENT STAGES ILLUSTRATED WITH A FUNNEL: - The top of the funnel represents the drug discovery phase. - High-throughput screening of thousands of compounds. - Hit to lead phase narrows down to hundreds of compounds. - Lead optimization phase progresses to dozens of compounds. - Candidate seeking phase dwindles to 1-3 compounds. - The bottom part of the funnel represents the preclinical development phase and culminates in different clinical trial phases. - **Preclinical Development** - Safety and tolerability in normal healthy volunteers and in two species. - **Phase I Clinical Development** - Safety and tolerability in patients. - **Phase II Clinical Development** - Early clinical POP. - **Phase III Clinical Development** - Definitive Clinical POP. ## THE DRUG DISCOVERY PHASE - Drug discovery is a process which aims at identifying a compound therapeutically useful in treating and curing a disease. - The process of drug discovery involves the identification of the candidates, Synthesis, characterisation, screening, and assays for therapeutic efficacy. ### STEP 1: TARGET IDENTIFICATION - Target identification is the key stage in the drug discovery. - A **drug target** is the specific binding site of a drug *in vivo* through which the drug exerts its action. A specific drug target might have the following characteristics: 1. The drug target is a biomolecule(s), normally a protein that could exist in isolated or as a complex modality. 2. The biomolecules have special sites that match others. 3. The biomolecular structure might change when the biomolecule binds to small molecules and the changes in structure normally are reversible. 4. Following the change in the biomolecule's structure various physiological responses occur and induce regulation of the cell, organ, tissue, or body status. 5. The physiological responses triggered by the changes in biomolecule structure play a major role in complex regulation and have a therapeutic effect on pathological conditions. 6. The expression, activity, and structure of the biomolecule might change over the duration of the pathological process. 7. Small molecules binding to the biomolecules are drugs. ### EXAMPLE - The knowledge that breast cancer is often estrogen-sensitive led to the development of aromatase inhibitors such as **anastrozole**, which prevents estrogen synthesis. ### STEP 2: TARGET VALIDATION - **Target validation** is the process by which the predicted molecular target is verified. - New drug target validation might be of great help not only to new drug research and development but also provide more insight into the pathogenesis of target related diseases. Basically, the target validation process might include five steps: 1. Discovering a biomolecule of interest. 2. Evaluating its potential as a target. 3. Designing a bioassay to measure its biological activity. 4. Constructing a high-throughput screening (HTS). 5. Performing screening to find lead compounds. ### STEP 3: LEAD DISCOVERY - A **Lead compound** in drug discovery is a chemical compound that has pharmacological or biological activity. - Different Methods of lead discovery are: #### Random Screening: - All compounds including synthetic chemicals, natural products of plant, marine and microbial origin from a given series is tested. - These are screened randomly in the hope of finding a compound with a specific biological activity. - This approach entered a new dimension with combinatorial chemistry & high through-put screening that allows considering the chemistry & the screening in an automated manner. - Antibiotics like streptomycin and tetracycline have been found out by this method. 2. **Non-random Screening:** It is a modified form of random screening which was developed because of budgetary and manpower restrictions. In this method only such compound with similar chemical structure are tested. 3. **Clinical observation:** Many a time a drug possess more than one pharmacological activities. The main activity is called as Therapeutic effect and while the rest of the action is called as side effects. Such compound may be used as lead compound for structural modification to improve potency of secondary effects. ### **EXAMPLE OF A LEAD (TAMiflu) BINDING TO THE PROTEIN TARGET (NEURAMINIDASE)** - An illustration depicts a drug-like substance attaching to a complex protein. ### RECENT ADVANCES IN DRUG DISCOVERY #### HIGH-THROUGHPUT SCREENING TECHNIQUE (HTS) - HTS is the process of assaying a large number of potential effectors of biological activity against targets (a biological event). - The methods of HTS are applied to the screening of genomics, proteins, and peptide libraries. - The goal of HTS is to accelerate drug discovery by screening large libraries often composed of hundreds of thousands of compounds (drug candidates) at a rate that may exceed 20,000 compounds per week. #### CHART COMPARING COMBINATORIAL AND TRADITIONAL SYNTHESIS - A table illustrates the parameters of Combinatorial Synthesis and Traditional Synthesis. - Row 1: **Reaction:** Many a times simpler (Combinatorial), Not so simple (Traditional). - Row 2: **Extreme condition i.e. at extreme temp./ pressure:** Avoid (Combinatorial), May possible to use (Traditional). - Row 3: **Use of highly Caustic reagent**: Generally avoid (Combinatorial), Possible to use (Traditional). - Row 4: **Use of inert atmosphere**: Avoid (Combinatorial), May use (Traditional). - Row 5: **Multistep Reaction**: Avoid (Combinatorial), Possible (Traditional). - Row 6: **Yield of compound**: Gives chemical library (Combinatorial), Gives single compound (Traditional). #### **FLOWCHART ILLUSTRATING THE PROCESS OF DRUG DEVELOPMENT** - A flowchart represents the stages of drug development from disease identification to drug marketed: - **Disease Identification** - **Target Identification & Validation** - **Synthesis of Compounds - Combinatorial Synthesis** - **High Throughput Screening** - **Lead Identification & Optimization** - **Preclinical Trials** - **Clinical Trials - Phases I - III** - **FDA Approval** - **Drug Marketed** - **Treats Disease** #### IMPORTANCE AND APPLICATIONS OF HTS - Selection of compounds from a vast number synthesized by combinatorial chemistry and other methods. - For lead generation for the treatment of a disease. - It is an efficient tool in studying biomolecular interactions and pathways. - It is highly efficient, fast, accurate and dependable in compound screening. - Useful in DNA sequencing. #### LIMITATIONS OF HTS - High cost. - Contamination of samples is possible. - Analysis of data and selection of relevant data from large moulds of data requires patience, professionalism, dedication and true expertise. #### GENOMICS - Genomics is the study of entire genomes. The intention of executing the sequencing and analysis of the entire human genome was to enable more rapid and effective identification of disease-associated genes and thereby provide it to drug companies with pre-validated targets. - An illustration depicts strands of DNA and a graph representing the advantages of nucleic acid bioassay miniaturization. #### PROTEOMICS - Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems. It is at the protein level that disease processes become manifest and at which most drugs act. - An illustration depicts a comparison between healthy cells and diseased cells, with a focus on the different protein expression that occurs in the diseased cells. It showcases drug discovery using disease-related proteins. ### STEP 4: LEAD OPTIMIZATION - Lead optimization is a process that begins with a compound that displays an interesting biological action and ends with the identification of the best analog. - Molecules are chemically modified and subsequently characterized in order to obtain compounds with suitable properties to become a drug. - Leads are characterized with respect to pharmacodynamic properties such as efficacy and potency *in vitro* and *in vivo*, Physiochemical properties, pharmacokinetic properties, and toxicological aspects. - **Potency:** Refers to the amount of drug required for its specific effect to occur. - **Efficacy:** Measures the maximum strength of the effect itself, at saturating drug concentrate ions. - **Pharmacokinetics:** It explains about "What the body does to the drug". It often divided into areas examining the extent and rate of absorption, distribution, metabolism, and excretion (ADME). - **Pharmacodynamics:** It determines the biochemical and physiological effects of drugs, the mechanism of drug action and the relationship between drug concentration and effect. It explains about "What the drug does to the body." - This process ideally requires the simultaneous optimization of multiple parameters and is thus a time consuming and is a costly step. - This is often the tightest bottleneck in drug discovery. However, by turning a biologically active chemical into an effective and safe drug, lead optimization contributes essentially towards added value in the drug discovery process. ### STEP 5: PRE-CLINICAL DEVELOPMENT - The aim of preclinical development is to satisfy all the requirements that have to be met before a new compound is deemed ready to be tested for the first time in humans. - Mainly done on Mice, Rabbit, Rat, Monkeys. - It is divided into four main categories: 1. **Safety Pharmacology:** Pharmacological testing to check that the drug does not produce any obviously hazardous acute effects, such as bronchoconstriction, cardiac dysrhythmias, blood pressure changes and ataxia. 2. **Preliminary toxicological testing:** To eliminate genotoxicity and to determine the maximum non-toxic dose of the drug (usually when given daily for 28 days, and tested in two species). As well as being checked regularly for weight loss and other gross changes, the animals so treated are examined minutely **post mortem** at the end of the experiment to search for histological and biochemical evidence of tissue damage. 3. **Pharmacokinetic and pharmacodynamic (PK/PD) testing.** 4. **Chemical and pharmaceutical development:** To assess the feasibility of large-scale synthesis and purification, to assess the stability of the compound under various conditions and to develop a formulation suitable for clinical studies. ### STEP 6: CLINICAL DEVELOPMENT - Clinical development proceeds through five distinct phases of clinical trials: 1. **Early Phase I (Formerly K/A Phase 0):** - A phase of research used to describe trials conducted before traditional phase 1 trials to investigate how a drug affects the body. - They involve very limited human exposure to the drug and have no therapeutic or diagnostic goals (for example, screening studies, micro dose studies). #### PHASE I - A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers. - The goal is to determine the drug's most frequent and serious adverse events and, how the drug is broken down and excreted by the body (Dosage). - It is performed on a small group (normally 20-80) of volunteers - often healthy young men but sometimes patients. - Approximately 70% of drugs move to the next phase. - Their aim is to check for: - Signs of any potentially **dangerous effects**, for eg: QT prolongation, a sign of potentially dangerous cardiac arrhythmias, is a common cause of failure in early development. - Tolerability - Pharmacokinetic properties - Pharmacodynamic properties - Clinical trials need to be performed under equally strict **Good Clinical Practice (GCP)** conditions. #### PHASE II - A phase of research to describe clinical trials that gather preliminary data on whether a drug works in people who have a certain condition/disease (that is, the drug's **effectiveness**). - For example, participants receiving the drug may be compared to similar participants receiving a different treatment, usually an inactive substance (called a placebo) or a different drug. **Safety** continues to be evaluated, and short-term adverse events are studied. - Phase II studies are performed on groups of patients (normally 100-300) for several months to 2 years. - Approximately 33% of drugs move to the next phase. #### PHASE III - A phase of research to describe clinical trials that gather more information about a drug's safety and effectiveness by studying different populations with disease and different dosages and by using the drug in combination with other drugs. - It is aimed at comparing the new drug with commonly used alternatives. These are extremely costly, difficult to organize and often take years to complete. - It is performed as double-blind, Randomised trials, commonly as multicenter trials on thousands of patients (300-3000). - Approximately 25-30% of drugs moves to the next phase. #### PHASE IV - A phase of research to describe clinical trials occurring after regulatory body of the country has approved a drug for marketing. - They include post market requirement and commitment studies that are required of or agreed to by the study sponsor. - These trials gather additional information about a drug's safety, efficacy, or optimal use. - Eg:- withdrawal of Rofecoxib (a cyclo-oxygenase-2 inhibitor) when it was found (in a phase III trial for a new indication) it increase the frequency of heart attacks.