PHM 2110 Medicinal Chemistry 1 PDF

PHM 2110-MEDICINAL CHEMISTRY 1 CHAPTER 1-Introduction Lecturer: Katherine Prasad, BSc School of Pharmacy Colleges of Health Science University of Guyana  Contents Objectives: At the end of this lecture students should be able to: ...

PHM 2110-MEDICINAL CHEMISTRY 1 CHAPTER 1-Introduction Lecturer: Katherine Prasad, BSc School of Pharmacy Colleges of Health Science University of Guyana  Contents Objectives: At the end of this lecture students should be able to:  Understand the concept ‘medicinal chemistry’  Define a drug  Identify the stages of drug development  List the phases of drug action  Identify the type of bonds that exist between drugs  Explain the SARS that exist in medical structures  Medicinal Chemistry This branch of chemistry is involved with the identification, design, synthesis and development of new drugs that are safe and suitable for therapeutic use. It entails:  Discovering new compounds with specific medical properties  Determine effect on biological processes  Altering the structure of the compound for optimum effect and reduced side effect This usually involves synthesizing and testing hundreds of compounds before a suitable compound is produced. It is currently estimated that for every 10 000 compounds synthesized one is suitable for medical use.  Pharmacology Microbiology Immunology MEDICINAL Genomics CHEMISTRY Pharmaceutics Spectroscopy Biology Organic Chemistry  Drug What is a drug? A compound that interacts with a biological system, and produces a biological response. An ideal drug should be: Selective Easily Effective administered Non-toxic Affordable However, in reality no ideal drug exist  Reason for discovering new drug Resistance and tolerance from the overuse of the same medication:  Increase metabolism of drug- the effectiveness of barbiturates decreases due to repeated dosing where the liver increases the production of enzymes for metabolizing the drug.  Down-regulation of receptors -occurs when repeated stimulation of a receptor results in the receptor being broken down. This results in the drug being less effective because there are fewer receptors available for it to act on. Side effect profile of the drug New drugs are required to combat drug resistance, even though it can be minimized by the correct use of medicines.  Drug discovery Designing a new drug- initiating a new project: Choose a disease- focus on a diseases that are important in the world e.g. migraine, diabetes, hypertension Choose a target- enzyme, receptor, nucleic acid. Allows to determine whether agonists or antagonists should be designed for a particular receptor or whether inhibitors should be designed for a particular enzyme. Target specificity and selectivity- the more selective a drug is for its target, the less chance there is that it will interact with different targets and have undesirable side effects.  Drug Development 1) Drug discovery- choice of a therapeutic agent with the identification , and production of new active compounds known as LEAD COMPOUNDS-starting point The synthetic compounds developed from a lead are referred to as its analogues The discovery of a new drug is part luck and part structured investigation. Today, many discoveries start with biological testing to determine the nature of the pharmacological activity. The screening technique may be random or focused.  Drug Development  In random screening programs all the substances and compounds available are tested regardless of their structures.  In focused screening procedures, specific structural types are tested. Once a compound is identified, it is isolated and used as a lead compound for the production of related analogues.  Drug Development WHERE TO FIND A LEAD COMPOUND? Plant life- flowers, trees Micro-organisms-bacteria, fungi Natural sources Animal-snakes Marine- corals, fishes Biochemicals -neurotransmitters Synthetic Chemical Synthesis Virtual Computer aided drug design  Sources of Lead Compounds Plant Extract- Quinine from Cinchona Plant Extract- Salicylic acid from Willow Bark tree  Sources of Lead Compounds Adrenaline- natural compound Salbutamol- analogue The natural substrate for a receptor/ enzyme can serve as a starting point for lead discovery  The future Lead compound Targets The past Targets Lead compounds The future  Drug Development 2) Optimization – modification of the lead compound to improve effect by:  Identify structure-activity relationship (SAR)- product is isolated and their structure and pharmacological activity is investigated to determine essential functional groups for binding.  Drug Development 2) Optimization – modification of the lead compound to improve effect by:  Identify the pharmacophore- the compound responsible for the physiological activity of a compound  Improve pharmacokinetic properties  Improve target interactions (pharmacodynamics)  Enhancing a side effect  Drug Development 3) Development – optimization of synthetic processes for mass production:  Patent the drug  Preclinical and clinical trials  Manufacture drug  Marketing  Phases of drug action PHARMACEUTICAL PHARMACOKINETIC PHARMACODYNAMIC Drug Drug Disintegration of available for Absorption available for absorption Distribution action Drug-receptor dosage form Dose Dissolution of Pharmaceutical Metabolism Biological interaction in target Effect availability Excretion availability tissue active substance Route of Drug Administration  Pharmacokinetic Phase Absorption is the passage of the drug from its site of administration into the plasma. Good absorption requires that a drug molecule has the correct balance between its polar (hydrophilic) and nonpolar (hydrophobic) groups.  Pharmacokinetic Phase Distribution is the transport of the drug from its point of absorption to its site of action. The main route is the circulatory system; however, some distribution does occur via the lymphatic system. Once a drug has reached the tissues, it can immediately be effective if its target site is a receptor situated in a cell membrane.  Pharmacokinetic Phase Distribution Drugs that are transported are dissolved in an aqueous medium of blood in a free form or bound to plasma proteins. Drug molecules that are bound to plasma proteins have no pharmacological effect until they are released from the proteins. However, it is possible for one drug to displace another from a protein if it forms a more stable complex with that protein. This may result in unwanted side effects, which could cause complications when designing drug regimens involving more than one drug.  Pharmacokinetic Phase Metabolism- biotransformation of the drug into other compounds referred to as metabolites. This occurs mainly in the liver. Metabolism of a drug usually reduces the concentration of that drug in the systemic circulation, which normally leads to either a lowering or a complete suppression of the pharmacological action and toxic effects of that drug. Exceptions are prodrugs, such as prontosil, where metabolism produces the active form of the drug.  Pharmacokinetic Phase Excretion- irreversibly remove a drug from the body during its journey to its site of action. It reduces the medical effect of the drug by reducing its concentration at its site of action Volatile or gaseous drugs are excreted through the lungs. The kidneys are the principal route by which drugs and their metabolites are excreted.  Binding The main molecular targets for drugs are proteins (mainly enzymes, receptors, transport proteins) and nucleic acids (DNA and RNA). The interaction of a drug with a macromolecular target involves a process known as binding  Intermolecular binding Binding occurs via various types of bonds:  Ionic or electrostatic bond- strongest of the intermolecular bonds  Takes place between groups that have opposite charges, such as a carboxylate ion and an aminium ion  Stronger in hydrophobic environments than in polar environments.  The strength of the ionic interaction is inversely proportional to the distance between the two charged groups  Intermolecular binding Hydrogen bond  A hydrogen bond takes place between an electron-rich heteroatom (oxygen or nitrogen) and an electron-deficient hydrogen.  The electron-deficient hydrogen is usually linked by a covalent bond to an electronegative atom.  Hydrogen bonds are a weak form of electrostatic interaction because the heteroatom is slightly negative and the hydrogen is slightly positive.  Intermolecular binding Van der Waals interaction  Van der Waals interactions also known as London forces are the weakest intermolecular force.  Involve interactions between hydrophobic regions of different molecules, such as aliphatic substituents or the carbon skeleton.  The strength of these interactions falls off rapidly the further the two molecules are apart.  Therefore, the drug has to be close to the target binding site before the interactions become important.  Solubility A drug usually exhibit a reasonable degree of both water and lipid solubility to pass through the membrane. An appropriate degree of water solubility will often improve drug distribution and drug action. Drugs that are sparingly soluble in water may be deposited en route to their site of action, which can clog up blood vessels and damage organs e.g. sulphonamides, tend to crystallize in the kidney, which may result in serious liver and kidney damage.  Solubility  The solubility of a compound depends on its degree of solvation in the solvent.  Consequently, the water solubility of an organic compound depends on the number and nature of the polar groups in its structure and size of its carbon– hydrogen skeleton.  The higher the ratio of polar groups to the total number of carbon atoms in the structure the more water soluble the compound.  The water solubility of a lead compound can be improved by : salt formation, by incorporating water solubilizing groups into its structure, especially those that can hydrogen bond with water, and the use of special dosage forms  Incorporation of water solubilizing group Alcohol Amine Amide Carboxylic acid The incorporation of polar groups, result in analogues with an increased water solubility. The formation of zwitterions by the introduction of either an acid group into a structure containing a base or a base group into a structure containing an acid group can reduce water solubility.  Structure-Activity Relationships (SARS) Compounds with similar structures to a pharmacologically active drug are often biologically active. This activity may be either similar to that of the original compound but different in potency and unwanted side effects or completely different than the original compound. These structurally related activities are commonly referred to as structure–activity relationships (SARS).  Structure-Activity Relationships (SARS) Structure–activity relationships are determined by making minor changes to the structure of a lead to produce analogues. These changes may be classified as changing  size and shape of the carbon skeleton  nature and degree of substitution  Structure-Activity Relationships (SARS) Changing size and shape-can be modified by changing the number of methylene groups in chains and rings, increasing/decreasing the degree of unsaturation and introducing/removing a ring system Introduction of new substituents- either occupy a previously unsubstituted position in the lead compound or replace an existing substituent.  Structure-Activity Relationships (SARS) CHANGING THE SIZE AND SHAPE OF LEAD COMPOUNDS TO PRODUCE NEW ANALOGUES  The number of methylene (CH2) groups in a chain or ring-increasing the number of CH2 groups in a chain can lead to micelle formation which can reduce drug activity  Structure-Activity Relationships (SARS) CHANGING THE SIZE AND SHAPE OF LEAD COMPOUNDS TO PRODUCE NEW ANALOGUES The degree of unsaturation-introduction of a double bond increases the rigidity of the structure and in some cases the possibility of E and Z isomers. The reduction of double bonds makes the structure more flexible.  Structure-Activity Relationships (SARS) CHANGING THE SIZE AND SHAPE OF LEAD COMPOUNDS TO PRODUCE NEW ANALOGUES Addition or removal of a ring-introduction of a ring may result in the filling of a hydrophobic pocket in the target, which can improve the binding of the drug to its target. The incorporation of larger ring systems may be used to produce analogues that are resistant to enzymic attack. Group Effect on lipophilic Change in Solubility Remarks character Methyl lipid , water Improves absorption Release from biological membranes more difficult. Changes nature and rate of metabolism. Fluorine, lipid water Improve ease of penetration of cell Chlorine membranes. Accumulate in lipid tissues. Hydroxy lipid water New centre for hydrogen (influence binding of the drug to the target) site. Increase rate of elimination of the drug by a new metabolic pathway and/or excretion Amino lipid water New centre for hydrogen bonding, Incorporation of aromatic amines is avoided as they are often toxic and/or carcinogenic Group Effect on lipophilic Change in Solubility Remarks character Carboxylic and Lipid ` Water Increases the ease of elimination. sulphonic groups Carboxylic acid group introduction into small lead molecules may change the type of activity of the analogue whilst sulphonic acid group incorporation does not normally change the type of activity.  Case-Study-Asthma Asthma is a common long-term condition that can cause coughing, wheezing, chest tightness and breathlessness. Asthma is caused by inflammation of the small tubes, called bronchi, which carry air in and out of the lungs. When an asthma sufferer comes into contact a trigger – the airways become narrow, the muscles around them tighten and there is an increase in the production of sticky mucus (phlegm).  Case-Study-Asthma Bronchodilators, make breathing easier by relaxing the muscles in the lungs and widening the airways (bronchi). Adrenaline is a natural bronchodilator produced at nerve endings to stimulate muscle activity. Adrenaline however also increases heart rate and blood pressure, making it unsuitable for treating an asthma attack.  Case-Study-Asthma Adrenaline was found to bind to three different receptors producing different effects. Receptor Effect Outcome α-receptors Increased blood pressure Unhelpful β1-receptors Increased heart rate and force Unhelpful β2-receptors Dilation of bronchi Helpful  Case-Study-Asthma To over come the side effects, an agonist is needed that is selective for the β2-receptor and activating only the dilation of the bronchi. Starting from adrenaline chemists altered the structure to select β2 activity and produce a longer lasting activity. Adrenaline  Case-Study-Asthma Isoprenaline The bulky group attached to the nitrogen improved β2 selectivity  Case-Study-Asthma Salbutamol Isoprenaline Salbutamol is found to have even better β2 selectivity since the group attached to the nitrogen atom is even bulkier. It also produces longer lasting effects than isoprenaline because of the replacement of the 3-hydroxyl group on the benzene ring. This modification slows down the metabolism of the drug in the body. Salbutamol is used effectively as a drug option for asthma