Understanding Medicinal Chemistry: A Student Study Guide

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Shireland Collegiate Academy**We aren't endorsed by this school

Course

CHEM 564

Subject

Chemistry

Date

Dec 11, 2024

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Uploaded by BaronReindeerPerson1623

3PY001 Orientation toPharmaceutical StudiesStudent Study Guide (2)The Chemistry of DrugsFacilitatorRequired ResourcesDr Mark HewittDr Matthew Palframan Dr Ben ButlerCompulsory: This study guide including all YouTubematerial and directed websitesStudy Guide 1 – especially acids and basesonwardsOptional: Graham l. Patrick, 2013, An Introduction toMedicinal Chemistry, 5th edition, OUPJ. Clayden, N. Greeves and S. Warren, 2012,Organic Chemistry, 2nd edition, OUPJ. Barber and C. Rostron, 2013,Pharmaceutical Chemistry, OUPLearning Outcomes1.Gain an insight into how and why medicines work in the body2.Understand how the physicochemical properties of a molecule can alter theeffectiveness of a drug

Table of ContentsMedicinal Chemistry.....................................................................................................3ADME (pharmacokinetics)........................................................................................4Lipinski’s Rule of Five (Drug Likeness).....................................................................5Molecular Weight......................................................................................................5Log P.........................................................................................................................6Octanol in log P Determination.............................................................................6The Effect of pH on Partitioning............................................................................7Solubility....................................................................................................................7Altering Solubility...................................................................................................8Predicting solubility................................................................................................9Summary.................................................................................................................10

Medicinal ChemistryThere are two import factors that need to be considered when we think about how todesign an effective drug.1.How the drug can effectively interact with the protein of interest.2.How the drug can reach the site of action on the body.The first is explained very nicely through this video, using the principles from the firststudy pack, with regard to the bonds and bonding interactions which can occurbetween two molecules:A basic introduction to drugs, drug targets, and molecular interactions:https://www.youtube.com/watch?v=u49k72rUdycThe second is often the most difficult hurdle and relies on the optimisation of thephysicochemical properties of the molecule. It is therefore important that you havean overview of the hurdles a drug must overcome after oral administration to reachthe site of action and be able to exert the desired biological effect. For this modulewe are only really going to consider oral administration of drugs (e.g. tablets,capsules, syrups, liquids), although it is important to note that drugs can beadministered in a variety of ways (e.g. inhalation, topically, injection etc.) and this islikely to be explored in more detail in your future studies.The hurdles associated with oral administration are clearly explained in the nextvideo: How do Drugs Work?https://www.youtube.com/watch?v=CtnKuLWFpQ4ADME (pharmacokinetics)This is often described as what the body does to the drug:Absorption:In order for a compound to reach its target in the body, it must pass intothe blood. Typically it must get through cell membranes (especially in the gut) beforeit can reach the target cells.Distribution:Once a compound is absorbed, it has to be distributed usually throughthe blood stream.Metabolism: Compounds begin to be metabolized as soon as they enter the body. Ifthe compound is orally delivered, there are enzymes in the GI tract and lumen thatwill start this process Most of the metabolism is carried out by the liver where thedrug goes immediately after being absorbed through the gut.

Excretion:After distribution and metabolism, the drug and its metabolites will beremoved from the body. It is important that a drug is metabolised and excreted toavoid toxicity associated with overdose.Lipinski’s Rule of Five (Drug Likeness)The physicochemical properties of drugs have significant implications when choosingappropriate dosage forms and routes of administration. In order to highlight drugs which may exhibit problems in terms of their oralabsorption(poor solubility and membrane permeation), Lipinski, following analysisof a large data set, developed a set of simple rules:PropertyValueMolecular weightShould be less than500Partition coefficient (Log Poctanol/water)Should be less than5Number of H-bond donorsShould be less than5Number of H-bond acceptorsShould be less than10An increasing number of rule violations predict that an absorption-relatedproblem is likely.The rule of five is commonly used to indicate the ‘drug-likeness’ of acompound. Molecular WeightLarge molecules tend to be poorly absorbed. However this rule is often violated bydrugs which are (or are related to) natural products e.g. Erythromycin.

Erythromycin is an antibiotic available as tablets, slow-release capsules, oralsuspensions, ophthalmic solutions, ointments, gels, and injections.Log P Partitioning (log P) is a measure of a compounds hydrophilic and hydrophobic natureand provides insights into a drugs bioavailability. The body is, in effect, a two phase system made up of aqueous and non-polar(lipid) components. A drugs affinity for different body components is critical. oIf a drug is too hydrophilic, it will show excellent water solubility, but itwill not be able to cross biological membranes since they havehydrophobic characteristics. oLikewise, excessive hydrophobicity is problematic since a drug wouldbe poorly water soluble and would enter, but not leave, cellmembranes. Hydrophobicity plays a major role in determining a drugs ADME profile(whichwe will look into in more detail later on)Hydrophobic characteristics are also often important in terms of receptorbinding.The absorption of oral formulations through the gastrointestinal (GI) tract is a goodexample. For a drug to pass into the bloodstream, it must pass through lipid bilayers(membrane) of the intestinal epithelium. The drug must be hydrophobic enough topartition into the lipid bilayer, but not so hydrophobic that it is unable to partition backout again.

This requires a drug to possess both hydrophilic and hydrophobic character and fallwithin a specific log P range. Octanol in log P DeterminationOctanol is routinely used as the non-polar solvent in log P determinations. This is because the structure of octanol resembles the approximateamphiphillic form of a phospholipid(with a polar head and hydrophobic tail). Due to this, octanol is used to represent the phospholipid bilayer of a cellmembraneand, as such, log P can indicate whether or not a substance maypass through a cell membrane and enter a cell.The Effect of pH on PartitioningSince partitioning is a balancing act between a compounds relative solubility in apolar and a non-polar solvent, pH is a significant factor to consider. As mentioned inthe first study guide, charged compounds are far more soluble in polar solvents thanthe uncharged (free) equivalents.

Therefore, the pH of a solution is critical since it will dictate whether acompound will be ionised or not, hence it’s affinity for an aqueous or oilyphase. This is particularly important as many drugs are weak acid and weak bases. Giventhe range of pH within the body the following is true with regards to partitioning:For weakly acidicdrugs Majority is UNIONISEDingastric fluid (pH 1-2)∴More likely to beabsorbed in the stomachMajority isIONISEDinintestinal fluid (pH 7-8)For weakly basicdrugs Majority is PROTONATEDingastric fluid (pH 1-2)∴More likely to beabsorbed in the smallintestineMajorityisDE-PROTONATEDin intestinalfluid (pH 7-8)SolubilityThe solubility of a compound in a given solvent is a function of its structure (andassociated physicochemical properties) as well as the experimental conditionsduring assessment. As discussed previously it is important that a drug has someaqueous solubility in order to be absorbed.Altering SolubilityIncreasing the temperatureof a system usuallyincreases the solubility ofsolids. oIncreases kinetic energy in the system, causing solute dispersion toincrease, and exposes solute to fresh solvent faster. oDissolution represents a change in physical state (solid to liquid) whichrequires energy (heat) to break the bonds present in the bulk solid. oFor solid and liquid systems, increasing the pressurehas no notableeffect on solubility. oHowever, for gasesdissolved in liquid, increasing pressure increasestheir solubility as they can form supersaturated solutions.oMelting point is often related to solubility. Solubility and melting point bothinvolve a phase change from a solid into a liquid. They both (to some extent)are dependent on the energy needed to break/form intermolecular bonds.In pharmaceutics, these factors are not normally of concernsince body temperature and pressure is not something thatcan be altered (36.5-37.5oC and 1 ATM).Of more interest is how structural properties/features of drugsinfluence their solubility.

oCompounds with high melting points usually show poor water solubilityand vice versa.oTherefore if you can make a compound with a lower melting point youare likely to increase water solubilityoMolecular shape and symmetry determines how well molecules can packtogether in the solid (crystal) state. Symmetrical, flat molecules can packtightly together with stronger intermolecular forces, resulting in higher meltingpoints and lower aqueous solubility then unsymmetrical molecules. oIncreasing molecular weight usually results in a decrease in water solubility.Increasing molecular weight equates to increased non-polar (hydrophobic)nature (e.g. increasing carbon content). oA general rule of thumb in the pharmaceutical industry is that drugswith molecular weights > 500 Da are likely to show reduced solubility.oCompounds with molecular weight above 1200 Da should be avoidedoHydrogen bonding abilityof a solute molecule can significantly affectsolubility. oThe addition of a hydrogen bond-donating group (e.g. hydroxyl (OH))or accepting-group (e.g. amide (NH2C=O)), usually increases solubilitysince it can form H-bonds with polar solvents. oHydrogen bonding ability is not always a favourable trait since stronghydrogen bonds between neighbouring solutemolecules can beformed. If these bonds are too strong, water cannot sufficientlyintervene and solubility is reduced.oPolar (ionisable) functional groupsincrease water solubility. For example,acids and bases can exist in charged forms that are much more soluble thantheir uncharged equivalents.You can alter the aqueous solubility of a compound by attaching differing functionalgroups. Taking the example of acetanilide below, you can see how substitutinghydrogen for various non-polar and increasingly polar substituents affects itssolubility.In lead development, the structure of many promising drug candidates are altered inthis manner to modulate (usually increase) aqueous solubility.

Predicting solubilityIt is also possible to predict water solubility using computational tools. Given theknow contributions certain structural features have on solubility, these tools breakdown a molecule into its component groups and combine these contributionstogether to generate a prediction. Some structural features will increase water solubility (e.g. polar groups)Other fragments will have a negative effect (non-polar groups).This means that you can use a computer to predict which compounds are likely to bemore successful and help prioritisation.SummaryYou should now appreciate why it takes so long to discover effective medicines, andthat it is necessary to find a molecule which:Bind to the desired target through intermolecular interactionsCan be absorbed and distributed around the bodyIs stable to the acidic conditions in the stomach (if taken orally)Can survive metabolism long enough to have a biological effectIs metabolised and excreted to minimise toxic effectsHas little/no toxicityCan be synthesised