![The first noted use of "serendipity" in the English
language was by Horace Walpole (1717–1792). In
a letter to Horace Mann (dated January 28th 1754)
he said he formed it from the Persian fairy tale
The Three Princes of Serendip, whose heroes
"were always making discoveries, by accidents
and sagacity, of things they were not in quest of".
The name stems from Serendip, an old name for
Ceylon (modern Sri Lanka), from Arabic
Sarandib, from Sanskrit Simhaladvipa which
literally translates to "Dwelling-Place-of-Lions
Island"[3]](https://image.slidesharecdn.com/drugdevelopment-240609041942-7b2aa874/85/Drug-Development-method-by-responsees-ppt-14-320.jpg)
![ In this phase broader range of assays on
different test systems are employed to compare the
potencies of various lead compounds to select the
one or more with greatest potential to be
developed into safe and effective medicine(s).
The intuitive approaches such as synthesis of
analogues and isomers and the modification of
ring systems are used for optimization. These
methods may rest on computer-assisted design,
such as identifying pharmacophores by molecular
modeling or optimizing activity by means of
SARs.
Pharmacophore [fahr´mah-ko-for″] the group of
atoms in the molecule of a drug responsible for the
drug's action.](https://image.slidesharecdn.com/drugdevelopment-240609041942-7b2aa874/85/Drug-Development-method-by-responsees-ppt-32-320.jpg)
Drug Development method by responsees .ppt
- 2. Drug Development:- Drug development may be defined as series of specialized events performed to satisfy criteria, internal (i.e. competitive industry benchmarks) and external (i.e. regulatory compliance), to produce a novel drug. Novel Drug:- The drug that does something valuable that presently not have been possible or that does safely what could previously have been achieved only with substantial risk.
- 3. At present, drug development consists of four distinct stages: 1- Drug discovery 2- Preclinical development 3- Clinical development 4- Manufacturing Cost and Time for the Drug Development:- Discovering and bringing one new molecule (drug) to the public typically costs a pharmaceutical or biotechnology company from $ 800 million to more than $ one billion and takes on average 10-15 years.
- 4. 1-2 years 1.2 Regulatory Approval Submission of full data and review by regulatory agencies DRUG DISCOVERY Target selection Lead-finding Lead optimisation Pharmacolo- gical Profiling 2-5 year 100 Projects Drug Candidate PRECLINICAL DEVELOPMENT Pharmacoki -netics Short-term toxicity Formulation Synthesis Scale-up 1.5 year 20 compounds CLINICAL DEVELOPMENT Phase I Pharmaco- kinetics, Tolerability side-effects in healthy volunteers Phase II Small-scale Trials in patients To assess efficacy & dosage Long-term Toxicology studies Phase III Large-scale Controlled clinical trials 10 5 2 Phase IV Post marketing surve- illance 1 Development Compound Regulatory Submission Drug approved for marketing 5-7 years The stages of development of a “typical” new drug, a synthetic compound being developed for systemic use.
- 5. Drug Discovery 1- Target Selection:- In the past, drug discovery programs were often based, successfully, on measuring a complex response in vivo, like, lowering of blood glucose level, lowering blood pressure or prevention of experimentally induced seizures without the prior identification of drug target. Now-a-days, the drug discovery process is often initiated with a decision to begin research on a new biological target. Studies are performed to characterize and define the target to establish the biological rationale. So target identification is the first step in drug development.
- 6. In the past, four main kinds of regulatory proteins were commonly involved as primary drug targets, namely: Receptors Enzymes Carrier molecules (Transporters) Ion channels Currently available therapeutic agents are believed to address about 120 distinct targets, but many proteins are thought to play a role in disease for which still no cognate drug. In the past thirty years, the evolution of molecular
- 7. medicine (including recombinant DNA technology) has led to a new pathway of drug discovery; Pharmacogenomics. This term encompasses all genes in the genome that may determine drug response, desired and undesired. Completion of Human Genome Project in 2001 yielded a minimum of 30,000 potential drug targets, although the functions of many of these genes remains unknown. It is expected that in future drug may be designed according to individual genotype, thereby enhancing safety as well as efficacy.
- 8. Now new drug could target at selected groups of patients based on their genetic make up (basis of pharmacogenetics). There are high expectations that pharmacogenetics/pharmacogenomics/ pharmacoproteomics will help in identification of subgroups of patients with a disease or syndrome based on their genotype and in targeting of specific drugs for patients with specific gene variants. Definition Proteomics is the systematic study of all of the proteins in a cell, tissue, or organism.
- 9. Proteomics:- A broad working definition of proteomics may be that proteomics is a high-throughput, data-rich, comprehensive, systematic, large-scale, and quantitative analysis of the expression of proteins and their associated peptides in biological/clinical samples obtained under specific (patho) physiological settings. Thus, proteomics provides a unique means to gain insights into the relative abundance of protein components present in complex biological samples, a capability that is important for the discovery of biomarkers and novel drug targets.
- 10. Pharmacoproteomics:- A term that is a synthesis of “pharmacology” and “proteomics”, refers to the comprehensive proteomics analysis that is relevant to novel drug target discovery, drug metabolism, as well as drug efficacy and toxicity. BIOMARKER:- In medicine, a biomarker is a term often used to refer to a protein measured in blood whose concentration reflects the severity or presence of some disease state. More generally a biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism.
- 11. Drug Discovery:- Drug discovery comes in several ways. 1- Old Approaches:- i-Natural Products:- a) plants:- Many plants and herbs contain substances that have useful pharmacological actions and new examples are continually being discovered. Examples: Morphine from Papaver somniferum. Atropine (Atropa belladonna), digoxin Antimalarial drugs from Artemisia species
- 12. b) Animals:- Several drugs have been discovered from the study of endogenous substances of animals. Examples are insulin (originally from dog pancreas). Anticoagulant from medicinal leech etc. Multinational companies now scour the world to find leads from microorganisms (in soil or sewage or even insects entombed) fungi, plants and animals. Developing countries in the tropics have luxuriant natural resources and are prominent targets in this search.
- 13. ii- Chemical Modification of a Known Molecules:- This approach obviously produces more agents with similar basic properties having little improvement in therapeutic value. It is in this area that “me too” and “me again” drugs are developed. iii- Serendipity:- Discoveries made by accidents and sagacity fall in this category. Examples penicillin by Alexender Fleming Sildenafil originally developed for antianginal property is being used in erectile dysfunction.
- 14. The first noted use of "serendipity" in the English language was by Horace Walpole (1717–1792). In a letter to Horace Mann (dated January 28th 1754) he said he formed it from the Persian fairy tale The Three Princes of Serendip, whose heroes "were always making discoveries, by accidents and sagacity, of things they were not in quest of". The name stems from Serendip, an old name for Ceylon (modern Sri Lanka), from Arabic Sarandib, from Sanskrit Simhaladvipa which literally translates to "Dwelling-Place-of-Lions Island"[3]
- 15. Hypoglycemic effect of sulfonamides in patients treating typhoid fever led to the development of structurally related sulfonylureas hypoglycemics. IV Metabolite of Existing Drug:- Some active metabolites of drugs have therapeutic value and advantage over the original parent compound e.g. Paracetamol is metabolite of phenacetin and it is not renotoxic. Sulfasalazine is metabolized to sulfapyridine (active antibacterial) and 5-aminosalicylic acid. V Random Screening:- Random screening of synthesized and natural product might result into finding of lead compound.
- 16. VI- Combination of Drugs:- Combination of known drugs may be exploited to obtain the additive, synergistic or repositioning of a known drug for a new therapeutic use, e.g. co-trimoxazole (combination of sulfamethoxazole and trimethoprim).
- 17. 2-New or Future Techniques of Drug Discovery:- I- Molecular Modeling:- The technique of molecular modeling by three-dimensional computer graphics allows the design of structures based on known and new molecules to improve their desired, and to eliminate undesired properties. This helps to create highly target selective compounds. II- Combinatorial Chemistry:- This branch of chemistry involves the random mixing and matching of large numbers of chemical building units (amino acids, nucleotides, simple chemicals) to create ‘libraries’ of all possible combinations. This technology can generate billions of new compounds that are initially
- 18. evaluated by automated robotic High-throughput screening devices. These devices can evaluate thousands of compound in a day. If any compound seems to have promising pharmacological activity, it is then subjected to traditional investigational laboratory methods, and the compound is manipulated to increase selectivity and/or potency. III- Biotechnology (Proteins as medicines):- Proteins are the target of most drugs and, in past, lack of technology was the main obstacle in exploitation of proteins (and peptides) as medicines.
- 19. With the invention of technology, there is great break through in this field. Biotechnology involves the use of recombinant DNA technology/genetic engineering to clone and express human genes, for example in microbial (Escherichi coli or yeast) cells, so that they manufacture proteins that medicinal chemists have not been able to synthesize. Such techniques can deliver hormones and autocoids in commercial amounts (like insulin, growth hormone, erythropoietins, cell growth factors and plasminogen activators, interferons, vaccines and immune bodies). Two approaches are being employed for this technology:
- 20. a. Transgenic Animals: Transgenic animals (that breed true for gene) are also being developed as models for human disease as well as production of medicines. b. Polymerase Chain Reaction: This is a method of amplification that does not require living cells; it takes place in-vitro and can produce (in a cost effective way) commercial quantities of pure potential medicines.
- 21. IV. Genetic Medicines In this technique synthetic oligonucleotides are developed to target sites, DNA sequences or genes (double-stranded DNA: triplex approach) or messenger RNA (the antisense approach), so that the production of disease – related proteins is blocked. These oligonucleotides offer prospects of treatment for cancers and viruses without damaging the healthy tissues.
- 22. An oligonucleotide (from Greek prefix oligo-, "having few, having little") is a short nucleic acid polymer, typically with fifty or fewer bases.
- 23. V. Gene Therapy:- Advances in molecular and cellular biology have described the proteins that mediate numerous disease processes, whereas the DNA technology provides direct access to the genes that control such events. Gene therapy has overcome the hazards encountered in maneuvering disease producing proteins. Gene therapy involves selective introduction of recombinant DNA into tissues to modify the genetic repertoire for therapeutic purposes.
- 24. VI- Immunopharmacology:- Knowledge of the molecular basis of immune responses has made easy to define the mechanisms by which cellular function is altered by the local hormones or autocoids in cancer, infections, autoimmune diseases or tissue transplant rejection. Thus agents that augment the immune response or selectively modify the balance of various components of immune system are also becoming important in the management of diseases like cancer, AIDS etc.
- 25. Vii- Positron Emission Tomography (PET):- This technique allows non-invasive pharmacokinetic and pharmacodynamic studies in previously inaccessible sites, e.g. the brain in living humans and animals. 2- Lead-Finding or Identification:- Lead Compound: A lead compound (i.e. the leading compound, not lead metal, for a successful new drug) in drug discovery is a chemical substance that possesses pharmacological or biological activity and has potential to treat disease. The chemical structure
- 26. of lead compound is used as a starting point for chemical modifications in order to improve potency, selectivity or pharmacokinetic parameters. Lead compounds are often found through High-Throughput Screening or secondary metabolites from natural sources. After the selection of target, discovery of a new lead substance represents the most uncertain stage in drug development program. Until the 1970s, the discovery of Lead Compound depended essentially on randomly occurring parameters such as accidental observation, fortuitous findings or laborious screening of a large number of molecules.
- 27. Since then more rational approaches, based on knowledge of structures of endogenous metabolites, the enzymes, the receptors, or nature of the biochemical disorder implied in the disease, have become available. Today human genome represents a great mine of potentially useful targets for which ligands have to be found. In 1997, it was estimated that the synthesis and screening of 100,000 compounds was required for the discovery of single good quality lead compound and this process could take up 2-4 years.
- 28. Secondary metabolites are organic compounds that are not directly involved in the normal growth, development, or reproduction of an organism. Secondary metabolites often play an important role in plant defense against herbivory and other interspecies defenses. Humans use secondary metabolites as medicines, flavorings, and recreational drugs.
- 29. In the past, compounds were either isolated from natural source or synthesized one by one and it used to take weeks or even months for each compound, but presently, the use of combinatorial chemistry allows formation of families of several thousands of related compounds simultaneously. The combined application of such High Speed Chemistry and High-Throughput Assay systems has reduced the lead finding period from years to few months. High-Throughput screening:- This is a method for scientific experimentation used in drug discovery and relevant to the
- 30. fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices and sensitive detectors, High Throughput Screening (HTS) allows a researcher to quickly conduct millions of biochemical, genetic or pharmacological tests. Through this process, the researcher can rapidly identify active compounds, antibodies or genes that modulate a particular pathway. The testing vessel of HTS is the microtitre plate. HTS robots can test up to 100,000 compounds per day. The Ultra High- Throughput Screening (uHTS) refers to screening in excess of 100,000 compounds per day.
- 31. A patent application would be filed for a novel compound (a composition of matter patent) that is efficacious, or for a new and non-obvious therapeutic use (a use patent) for a previously known chemical entity. Lead Optimization:- Lead optimization aims at increasing the potency of lead compound(s) at target site and to optimize it with respect to selectivity and metabolic stability.
- 32. In this phase broader range of assays on different test systems are employed to compare the potencies of various lead compounds to select the one or more with greatest potential to be developed into safe and effective medicine(s). The intuitive approaches such as synthesis of analogues and isomers and the modification of ring systems are used for optimization. These methods may rest on computer-assisted design, such as identifying pharmacophores by molecular modeling or optimizing activity by means of SARs. Pharmacophore [fahr´mah-ko-for″] the group of atoms in the molecule of a drug responsible for the drug's action.
- 33. Lead optimizing studies are conducted in animal models (in vivo) and in cells in the test tube (in vitro) to explore pharmacokinetics and pharmacodynamics in different clinical conditions similar to humans. Occurrence of untoward effects and evidence of genotoxicity is also studied in animals. It can take up to 5 years for the completion of this phase. Infact very few molecules, after the completion of lead optimization, proceed to next stage of preclinical development.
- 34. Preclinical Development (Studies in animals):- In the preclinical stage of drug development, an investigational drug (optimized Lead Compound) must be tested extensively in the laboratory models to ensure that it will be safe to administer to humans for first time. This testing may be completed in 1-5 years, however shorter periods are predicted. The work of this stage falls into following categories. i- Pharmacodynamics:- The preclinical laboratory tests document the
- 35. effect of investigational drug (optimized lead compound) in living organisms (in-vivo) in cells in the test tube (in-vitro) or even in silico. The objective is to investigate the actions relating to the proposed therapeutic use and to find potential undesirable effects on physiological functions. These tests are performed to check that the drug does not produce any hazardous acute effects, such as bronchoconstriction, cardiac dysarrhythmias, blood pressure changes and ataxia (this is termed safe pharmacology).
- 36. ii- Pharmacokinetics:- The pharmacokinetics testing includes studies on absorption, distribution, metabolism (biotransformation) and elimination in animals. The program is designed to allow comparison and extrapolation between animals and humans. iii- Toxicology:- Acute (single dose), chronic and sub-chronic (repeat dose) toxicity studies are carried out to characterize toxicological profile of the drug and to reveal physiological and/or histopathological changes induced by drug.
- 37. Generally, test be performed in two relevant species, based on pharmacokinetic profile, one a rodent and one non-rodent/ the duration depends on the clinical use and is defined by Regulatory Agencies (standard charts). The studies are used to determine maximum non-toxic dose, effect on weight, histological and biochemical evidence of tissue damage (post-mortem) and other gross changes. iv- Genotoxicity:- A standard battery of investigational tests is used to study changes that a drug causes in genetic material of individuals or cells.
- 38. v- Carcinogenicity:- If a medicinal product is expected to be used for prolonged (about six months) either continuously or repeatedly, studies are recommended to determine the carcinogenic potential of new drug. vi- Reproductive & Developmental Toxicity:- These tests study effects on adult male or female reproductive functions, toxic and teratogenic effects at all stages of development from conception to sexual maturity and latent effects when investigation drugs are given to the
- 39. female during pregnancy. Embryo/fetal toxicity studies are normally conducted on two mammalian species. vii- Chemical & Pharmaceutical Development:- During preclinical development, the structure, physical and chemical characteristics and stereochemical identity of the new drug are fully characterized. Appropriate bioanalytical methods are developed to assay the drug and its metabolites in body fluids. Stability study data of compound are collected.
- 40. All the results of preclinical tests are used by experts to assess the feasibility of large scale synthesis and purification, to assess the stability of the compound under different conditions and to develop a suitable formation (at least stable for six months) to start clinical studies. How are Investigational Drugs Tested in Human? Testing of an investigational drug begins with submission of information about the drugs and application for permission to begin administration to healthy volunteers.
- 41. Investigational New Drug (IND)/Clinical Trials Exception (CTX)/Clinical Trials Authorization (CTA) Application:- INDs (in the U.S.A.) CTXs (in the U.K.) and CTAs (in Australia) are examples of requests submitted to appropriate regulatory authorities for permission to conduct investigational research in humans. This research can be testing of a new dosage form or new use of a drug already approved to be marketed. In addition to obtaining permission from appropriate regulatory authorities, an institutional or Independent Review Board (IRB) or ethical advisory board must approve the
- 42. protocol for testing as well as the informed consent documents that volunteers sign prior to participating in a clinical study. An IRB is independent committee of physicians, community advocates and others that ensures that a clinical trial is ethical and the rights of study participants are protected. “ The regulatory authority may refuse permission or require further work to be done before granting permission|”.
- 43. Clinical Trial Synonyms:- Clinical study, interventional trial, medical research, clinical investigation, research study. Definition:- Although there are many definitions of clinical trials, they are generally considered to be biomedical or health-related research studies in humans that follow a pre-defined protocol. A clinical trial may be defined as a prospective carefully designed biomedical or behavioral research performed in human subjects to investigate safety, efficacy & effectiveness
- 44. of new drugs or combination of drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioral treatments, process-of-care changes and preventive care to improve the diagnosis of disease and quality of the life of the patient. Types of Clinical Trials 1- Treatment Trials:- In treatment trials experimental treatments, new drugs, combination of drugs, new approaches to surgery or radio-therapy etc are tested.
- 45. 2- Prevention Trials:- This type of trials look for better ways to prevent disease in persons who never had the disease or to prevent the reoccurrence of the disease.. These approaches include vaccines, medicines, minerals, vitamins or changes in life-style. 3- Diagnostic Trials:- These trials are performed to search for better tests or procedures for diagnosis of a particular disease or condition. 4- Screening Trials:- These are conducted to find ways and tests to detect certain diseases or health conditions.
- 46. 5- Supportive Care Trials (Quality of life trials):- These trials are conducted to find ways to improve comfort and quality of life of individuals with chronic illness.
- 47. Control Study:- A study in which the investigational drug is compared with a treatment that has known effects. The control group may receive either no drug, placebo or standard treatment. Consent:- In any study on human beings, each subject must be fully informed of the aims, methods, sources of funding any possible conflicts of interest, institutional affiliations of researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail.
- 48. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has completely understood the information, the physician then should obtain the subject’s freely given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non- written consent must be formally documented and Witnessed - Article 22, Declaration of Helsinki.