There are lots of processes of creating new drugs, where we may mainly distinguish between drug discovery and drug development. Drug discovery comes about in several different ways. The method is to subject new chemical entities to a set of screening tests designed to detect different types of biological activity. These include in Vitro screens as well as in Vivo screens. The history of drug discovery has changed gradually. Before 1990, medicines were produced by chemical synthesis or were isolated from existing compounds exhibiting poly-pharmacology or side effects, such as plants and herbs. Also, screenings were carried out through low throughput screening. More recently, the understanding of human receptors and substances which cause specific activity has proceeded, so this led to new drugs, such Cimetizine and Ranitizine. The studies of DMPK and ADME have progressed as well, so the studies were applied to drug discovery. In addition to that, the change from low throughput screening to high throughput screening allowed mass screening. Since 2000, the incredible advance of understanding of the human genome has led to novel medicines, such as Aranesp, Epogen, and Enbral, which are more biological than before. Toxicology developed and has been adapted to drug discovery as well. At the same time, attempts with using computers are increasing. As I mentioned above, the method of finding lead compounds has changed. Nowadays, main six methods to find lead compounds are becoming popular. Firstly, it is to improve existing drugs. Secondly, it is to create new drugs on the basis of natural products. Also, rational drug design using protein crystallography is becoming popular. The rest is high throughput screening, fragment screening, and virtual screening. In addition, there are the main two methods of designing structures, which are structure based design and ligand based design respectively. Targets of finding new lead compounds are mainly eight targets, which are receptors, enzymes, ion-channels, nuclear receptors, kinases, bacterial/viral targets, human genome, and others. The process of drug discovery is complex, so it takes 4 to 8 years to finish it. In the process of drug discovery, the small structural changes of chemicals sometimes cause large changes and effects. For instance, propranol shows both β1 andβ2 adrenoceptor selectivity. On the other hand, atenolol shows only β1 adrenoceptor selectivity. The structural differences between propranolol and atenolol are small, but their showing effects are different respectively.
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Once a new chemical compound has been discovered, drug development has to be carried out, culminating in its being licensed for use and marked. Preclinical tests on isolated tissues and in animals should ensure that the drug has the required mechanism of action and at least in animals will produce appropriate system responses. At this stage, the new drug will be tested against standard drugs in comparative assays. Toxicity tests in animals should in most cases allow some prediction of toxic effects in humans. In comparisons of drugs used clinically, potency does not necessarily relate directly to therapeutic usefulness. It is important to consider also the maximum achievable response and the incidence of unwanted effects. Clinical testing in humans involves four phases. Phase 1 is the measurement of pharmacological activity, pharmacokinetics and side effects in healthy volunteers. Phase 2 is pilot studies in small groups of patients to confirm that the drug works on the target condition and to establish the dosage regimen to be used in phase 3. Phase 3 is formal clinical trials in a large number of patients to determine the incidence of unwanted effects. Phase 4 is post marketing surveillance to establish efficacy and toxicity in general use. The detection of rare, adverse effects is most likely to occur in this phase. It takes 5 to 8 years to finish this stage, and costs much money than drug discovery stage.
It takes about 10 to 12 years from an idea to marketable drugs totally. Also, it takes approximately 800 million dollars to develop one new drug.
The duration of a drug's patent from the time of its registration with the UK Patent Office is 20 years. Therefore, pharmaceutical industries have to recoup their investment and make a profit, some of which will spend researching and developing other drugs. After a drug's patent expired, other pharmaceutical companies can make and sell the quite similar drug which is called a generic drug. As a result, the price often drops significantly. As a generic drug has become popular among people due to the price and the efficacy, generic drug's market is growing rapidly.
The definition of medicinal chemistry
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Medicinal chemistry is a chemistry based on discipline which is involved in aspects of biological, medical and pharmaceutical science. Also, it is concerned with the invention, discovery, design, identification and preparation of biologically active compounds. The chemistry is a study of their metabolism, mode of action at a molecular level, and relationships between chemical structure and activity.
The role of pharmacokinetics in drug discovery and drug development
Pharmacokinetics is the science of exploring the changes in drug concentrations throughout the body with time. It is important to understand the time course of drug effects. The time course of drug action usually follows that of the concentration at the target site. There are 4 main phases in the pharmacokinetic process, which are absorption, distribution, metabolism, and excretion. Drugs can be administered through the gut or by other route, which is called absorption. Most drugs don't spread rapidly throughout the whole of body water. A drug's penetration into these compartments is indicated by its volume of distribution that would be required to hold the amount of drug in the body at the measured plasma concentration. The plasma membrane of the cells constitutes a hydrophobic lipid barrier and drug permeation can occur by direct distribution through the lipid and carrier mediated transport. Diffusion of a drug depends on its concentration gradient and its diffusion coefficient. The concentration gradient established within the cell membrane depends on the drug's lipid/water partition coefficient. This is estimated by the drug's distribution between water and a simple organic solvent. Most drugs are ionised in aqueous solution. The ionised form is hydrophilic, so the ionisation impedes passive membrane permeation. When a drug enters the body, it is subjected to the processes that have been developed for dealing with toxic foreign molecules, which are called metabolism and excretion. The liver is the main site of drug metabolism, and the kidney is the main site of excretion.
There are some important terms in pharmacokinetics, which are half-life, AUC, and drug clearance. Half-life is the time taken for any given plasma concentration to decrease by 50%. AUC is a measure of the extent of absorption. Drug clearance is defined as the volume of plasma cleared of drug per unit time.
Drug metabolism in drug discovery
The main purpose of drug metabolism is to cause detoxification. Metabolism involves two main processes. Firstly, the molecule is made more hydrophilic to reduce the possibility of reabsorption in the renal tubules. Secondly, it is conjugated to reduce its effects and aid excretion. As I mentioned above, there are two phases of metabolism. Phase â… is mainly oxidative reactions, such as oxidation, reduction, and hydrolysis. The oxidation of a drug requires the cytochrome P450 which is the major enzyme. Phase â…¡ is conjugation reactions with sugar residue, such as glucuronidation, glycosidation, and sulfation. UDPGT is the main enzyme at this stage. Interestingly, there are species differences in metabolism. For example, lidocaine is metabolised to 4-hydroxylidocaine by hydroxylation in rats. On the other hand, lidocaine is metabolised to monoethylglycinexylidide by deethylation in dogs or men. The main reason why these differences occurred is the difference of enzymes between species. There are some particular enzymes in men and dogs, but there may be not the enzymes in rats. When the situation happens, species differences occur in metabolism.
The role of pharmacology in drug discovery
Pharmacology concerns the study of how drugs affect the function of host tissues or combat infectious organisms. In most cases, drugs bind selectively to target molecules within the body, usually proteins but other macromolecules as well. The main drug targets are receptors, enzymes, ion channels, and transporters. It is generally desirable that a drug should have a higher affinity for its target than for other binding sites. One of the main roles of pharmacology in identifying new drugs is drug target identification with using compounds known pharmacological properties to identify new target mechanisms, and identifying new receptors, ion channels, transporters, and enzymes. Receptors are protein molecules in or on cells that act as recognition sites for endogenous ligands such as neurotransmitters, hormones, inflammatory mediators. Many drugs used in medicine make use of these receptors. The effect of a drug may produce the same responses to an endogenous ligand or prevent the action of an endogenous ligand. A drug that binds to a receptor and activates the cell's response is termed an agonist. A drug that reduces or inhibits the action of an agonist is termed an antagonist. Some drugs produce the maximum response that the tissue can give. These are termed full agonists. Other drugs may not give the maximum tissue response in any concentration, which is called partial agonists. A drug shifts the equilibrium in favour of the non active form, so reducing background activity. Such drugs are referred to as inverse agonists. An antagonist is defined as a drug that reduces the action of an agonist. There are three main antagonism mechanisms, which are competitive antagonism, irreversible antagonism, and non-competitive antagonism. A competitive antagonist binds to the receptor and prevents the binding of an agonist. If the antagonist binds reversibly, then the effect of the antagonist can be overcome by raising the concentration of the agonist so that it competes more effectively for the binding sites. In irreversible antagonism, the antagonist binds irreversibly, reducing the number of receptors available for binding. In non-competitive antagonism, the antagonist does not block the receptor itself but blocks the signal transduction process initiated by receptor activation. Enzymes catalyse a chemical reaction, so convert substrates to products. In most cases, enzymes are proteins, and their targets are intracellular. Ion channels are fundamental membrane proteins, and convey ions across cell membranes. There are three main types of ion channel, which are voltage-gated channels, ligand-gated channels, and G-protein regulated channels. Voltage-gated channels are closely involved in ion gradients, and make the tissues excitable. Ligand-gated channels consist of a number of transmembrane subunits. The channel governs fast cell to cell communication. G-protein regulated channels modulate the excitability of excitable tissue. Transporters are proteins which can penetrate a cell membrane without modifying it, and transport substances. Drugs can modify this action by blocking a binding site, or acting as a false substance, and being transported into a cell.
The importance of oral administration and oral bioavailability
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Oral administration is the most convenient and acceptable route, because of the importance from the point of view of patients. It is much easier for patients to take medicine orally than taking by other routes. The important factors of oral drugs are potency, selectivity, rapid dissolution, and rapid transfer across the membranes of the gastrointestinal tract, low clearance, absence of dose independent and time independent in pharmacokinetics, and no interaction with other drugs.
Oral bioavailability is the proportion of the orally administered dose that reaches the systemic circulation. Incomplete release from the dosage form, destruction within the gut, poor absorption and first-pass elimination are important causes of low bioavailability. There are two main factors controlling oral absorption, which are physical barriers and biological barrier. Physical barrier comprises solubility, ionisation, lipophilicity, drug formulation, and interaction with other substances. As I discussed above, solubility, lipophilicity, and ionisation are closely related to absorption. Drugs must dissolve to establish a concentration gradient for absorption, the rate and extent of absorption depending on the pharmaceutical formulation. Rapid absorption of a drug requires its disintegration into small particles. In general, food will slow absorption by reducing the drug's concentration. On the other hand, biological barriers comprise efflux, transporters, and metabolism. Efflux is a biological reaction which forces out unnecessary substances. The reaction prevents drugs from entering inside of a cell. Metabolism is one of the biological barriers, because of different enzymes which are mainly CYP 450. Transporters are one of biological barriers, but the role of transporters preventing drugs from entering an interior cell is not clear now.
The example of drugs
Histamine is a mediator in both acute inflammation and the immediate hypersensitivity response. There are two main types of histamine receptor which are H1 and H2 receptors. Antihistamine drugs can target each receptor type. The main physiological aspects of the gastrointestinal tract are gastric acid secretion. The excess of gastric acid secretion cause peptic ulcers. In peptic ulcer, the balance between gastric acid secretion and mucosal-protective mechanisms is altered. The main approach to peptic ulcer is drugs used to reduce acid secretion. The H2 receptor antagonists, Cimetizine, Ranitizine, reduce gastric acid secretion in response to histamine, gastrin, and food. The proton pump is responsible for the secretion of gastric acid into the stomach. Therefore, the proton pump inhibitors show the effect of reduction in the secretion of gastric acid.
Antibacterial drugs are compounds used to treat bacterial infections. There are some targets for antibacterial drugs, such as cell wall, nucleotide mechanism, and protein synthesis. One of the important targets is cell wall which provides support for the membrane. Its main constituent is peptidoglycan which is an excellent target for drugs. Drugs affecting peptidoglycan synthesis include penicillins and penicillin G.
I learned the basis of drug discovery and development through these lectures, and I found the importance of medicinal chemistry, such as pharmacology and pharmacokinetics. It is essential to understand medicinal chemistry for discovering and developing novel and ideal drugs. At the same time, I feel we should consider discovering and developing drugs from the point of view of patients as well.