Medicinal Chemistry I 1435h

Medicinal Chemistry I 1435h
Tareq Abu-Izneid 13/04/2017 Medicinal Chemistry I 1435h Topic 1: Drug Structure & Pharmacological Activity Dr. Munjed Ibrahim PHM320-Topic-3-Drug Structure and Biological Activity

Resources Reading Suggested additional reading Text
Foye, Lemke & Williams, 6thed, Chapter 2 Foye, Williams & Lemke, 5thed, Chapter 2 Suggested additional reading An Introduction to Medicinal Chemistry, Patrick L. G., 3ed Cairns Chs 1 & 2 Delgado & Remers Ch 2, pp , Foye, 4th ed Chs 3 & 4 Watson Ch 2

Objectives Relationship of Functional Groups to Pharmacological Activity (SARs) Physiochemical Properties of drug molecules Acid - base properties of drug molecules pH and pKa (Henderson-Hassalbach Equation) ionisation and absorption Water and lipid Solubility (hydrogen and ion bonds) Predicting water solubility Empirical approach Analytical Approach Partition coefficient absorption/distribution Stereochemistry and pharmacological activity Optical isomerism (enantiomers and distereomers) Conformation isomers Geometric isomers (cis and trans) Isosterism and Bioisosterism drug design

Sites of Drug Action Enzyme inhibition 2. Drug-Receptor interaction
Tareq Abu-Izneid 13/04/2017 Sites of Drug Action ENZYME SUBSTRATE Enzyme inhibition Enzyme inhibition may be reversible or non-reversible; competitive or non-competitive 2. Drug-Receptor interaction A receptor is the specific chemical constituents of the cell with which a drug interacts to produce its pharmacological effects This is usually through specific drug receptor sites known to be located on the membrane 3. Non-specific interactions Drugs act exclusively by physical means outside of cells These sites include external surfaces of skin and gastrointestinal tract. Drugs also act outside of cell membranes by chemical interactions Neutralization of stomach acid by antacids is a good example PHM320-Topic-3-Drug Structure and Biological Activity

Tareq Abu-Izneid 13/04/2017 Mode of Drug Action It is important to distinguish between actions of drugs and their effects. Actions of drugs are the biochemicals, physiological mechanisms by which the chemical produces a response in living organisms. The effect is the observable consequence of a drug action. For example, the action of penicillin is to interfere with cell wall synthesis in bacteria and the effect is the death of bacteria One major problem of pharmacology is that no drug produces a single effect. The primary effect is the desired therapeutic effect. Secondary effects are all other effects beside the desired effect which may be either beneficial (good) or harmful (side effects, bad!!). Drugs are chosen to exploit differences between normal metabolic processes and any abnormalities, which may be present. Since the differences may not be very great, drugs may be nonspecific in action and alter normal functions as well as the undesirable ones, this leads to side effects The biological effects observed after a drug has been administered are the result of interaction between that chemical and some part of the organism. Mechanisms of drug action PHM320-Topic-3-Drug Structure and Biological Activity

Mechanisms of Actions of Drugs
Tareq Abu-Izneid 13/04/2017 Mechanisms of Actions of Drugs The fundamental mechanisms of drug action can be distinguished into following categories ENZYME SUBSTRATE 1. Through Enzymes Enzymes are very important targets of drug action because almost all biological reactions are carried out under the influence of enzymes. Drugs may either increase or decrease enzymatic reactions. Ex: Physostigmine and neostigmine compete with acetylcholine for cholinesterase 2. Through Receptors A large number of drugs act through specific macromolecular components of the cell, which regulate critical functions like enzymatic activity, permeability, structural features, template function PHM320-Topic-3-Drug Structure and Biological Activity

Receptors and Drug Action
Binding site Binding regions Binding groups Pharmacological response Intermolecular bonds Binding site Drug Macromolecular target Drug Bound drug Macromolecular target Unbound drug An Introduction to Medicinal Chemistry, Patrick, Third Edition

Drug-Receptor Interactions
vdw interaction Drug Phe H-bond Active site Ser O H ionic bond Asp CO2 receptor Receptors/enzymes are proteins, so they are amino acids (Asp, Phe, Ser) amino acids contain: carboxylic acids (ionic interaction) amines (ionic interaction) hydroxyl (hydrogen bond) An Introduction to Medicinal Chemistry, Patrick, Third Edition

Mechanisms of Actions of Drugs
Tareq Abu-Izneid 13/04/2017 Mechanisms of Actions of Drugs 3. Chemical Properties The drugs react extracellularly according to simple chemical reactions like neutralization, chelation, oxidation etc. Aluminium hydroxide neutralizes acid in stomach Toxic heavy metals can be eliminated by chelating agents like EDTA, BAL, penicillamine etc. PHM320-Topic-3-Drug Structure and Biological Activity

Functional Groups and Pharmacological Activity (Agonist, Antagonists)
Tareq Abu-Izneid 13/04/2017 Functional Groups and Pharmacological Activity (Agonist, Antagonists) ENZYME SUBSTRATE If acetylcholine interacts with its receptor, then molecules that are structurally similar to acetylcholine would also interact with the receptor Antagonists are generally larger in size than the natural substrate acetylcholine Antagonist: A drug which attenuates the effects of an agonist. Antagonism can be competitive and reversible (i.e. it binds reversibly to a region of the receptor in common with the agonist.) or competitive and irreversible (i.e. antagonist binds covalently to the agonist binding site, and no amount of agonist can overcome the inhibition). Other types of antagonism are non-competitive antagonism where the antagonist binds to an allotter site on the receptor or an associated ion channel. agonist: agents that elicit a maximal biological response partial agonist: agents that elicit a response, however, the maximum response obtained is less than that of an agonist (e.g. the physiological legend) antagonist: agent that binds (occupies the receptor) but does NOT elicit a response (antagonists can block an agonist from binding to the receptor); as with an enzyme inhibitor This is sort of a “lock & key” approach, wherein if you stop acetylcholine from binding to its receptor (by using another molecule that is similar in structure) then you will stop the effect of acetylcholine i.e. acetylcholine causes muscles to contract, if you stop it from binding to its receptor, muscles will therefore relax PHM320-Topic-3-Drug Structure and Biological Activity

Functional Groups and Pharmacological Activity
One feature that soon became apparent to the early scientists was that small changes in structure resulted in significant changes in biological activity: Crum-Brown & Fraser (1869) postulated that “muscle-relaxant activity” was related to quaternary ammonium groups (this was later proved wrong when acetylcholine was discovered)

Functional Groups and Pharmacological Activity
The discovery of acetylcholine (& its activity) prompted questions as to how a given functional group could have two different biological activities In the early 20th century, scientists speculated that this could be achieved if “drug receptors” were present If acetylcholine interacts with its receptor, then molecules that are structurally similar to acetylcholine would also interact with the receptor

Physiochemical Properties
Acid-Base: Conjugate pair theory Common acidic and basic functional groups W&L Table 2.1 and 2.2 respectively Shows acids and their conjugate bases together with pKa Be able to identify these from structures

Acidic groups Table 2.1 (page 29)
Acidic groups (page 29)

Basic groups Table 2.2 (page 30)

Neutral groups Table 2.3 (page 30)

Physiochemical Properties – Acids & Bases
The human body is composed of ~75% water (55 L of water) For an average drug (MW ~200; dose = 20 mg), this equates to a drug concentration of ~1.8 x 10-6M (i.e. a very dilute solution!) For dilute solutions we use the Brönsted–Lowry theory to predict the behaviors of acids & bases An Acid is any substance capable of yielding a proton (H+) A base is any substance capable of accepting a proton (H+) Please refer to Table 2.1 (pg. 29, Foye), Table 2.2 (pg. 30, Foye), and Table 2.3 (pg. 30, Foye)

Physiochemical Properties – Acids & Bases
Some drugs have both acidic and basic functional groups, and therefore can act as a base, an acid, or amphoteric (= both acidic & basic properties) Ciprofloxacin The location of the compound in the body will determine the overall charge of the compound

Relative Acid Strength (pKa) (Henderson–Hassalbach)
Henderson-Hasselbach Equation relates pH and pKa (acid strength) This equation (the Henderson–Hassalbach eqn) allows us to calculate the percent ionisation of a given molecule at a given pH since pKa is a constant for a given molecule, at a known pH (e.g. physiological) the concentration of the acidic and basic forms of a given drug will be able to be calculated But why is this important?? percent ionisation (clue to absorption of drug and activity/interactions)

Relative Acid Strength (pKa)
Look at the sulphonamides (antibacterial) Why is the following true? These compounds are only active in their ionised forms Despite only minor differences in half-life and lipo-solubility, there is a huge difference in activity This is due to their respective pKa values: For sulfadiazine, at pH 7.4 it is ~80% ionised For sulfanilamide, at pH 7.4 it is only 0.03% ionised The difference in pKa is due to the electron withdrawing nature of the sulfonamide nitrogen substituent, thereby stabilising the ionised form:

Ionisation of Drugs For an acid drug: For a basic drug:

Example: %ionisation for aspirin
pKa of aspirin (acetylsalicylic acid) is 3.5 Physiological pH = 7.4 For an acid drug

Rule of Thumb (acids) pH = pKa+ 4 Weak acids
pH = pKa compound ~ 50% ionised pH = pKa + 1 compound ~ 90% ionised pH = pKa + 2 compound ~ 99% ionised pH = pKa + 3 compound ~ 99.9% ionised pH = pKa + 4 compound ~ 99.99% ionised pKa of aspirin is 3.5 Physiological pH = 7.4 pH = pKa+ 4 %ionisation= 99.99%

Rule of Thumb (bases) pH = pKa- 2 Weak bases
pH = pKa compound ~50%ionised pH = pKa compound ~ 90% ionised pH = pKa compound ~ 99% ionised pH = pKa compound ~ 99.9% ionised pH = pKa compound ~ 99.99% ionised pH = pKa- 2 pKa of phenylpropanolamine is 9.4 Physiological pH = 7.4 %ionisation= 99% ionised

Physical Properties (water and lipid solubility)
Tareq Abu-Izneid 13/04/2017 Physical Properties (water and lipid solubility) Partition coefficient lipophilic vs. hydrophilic character of drug determines water solubility of drug substances affects drug distribution confers target-drug binding interactions Ratio of the solubility between lipid (octanol and water) PHM320-Topic-3-Drug Structure and Biological Activity

Water Solubility

Water Solubility Given that we are ~75% water, the solubility of a drug in water directly affects the route of administration, distribution, and elimination (ADME). The most important two key factors that influence this are: Hydrogen bonding: more H-bonds =>  solubility Ionisation: dissociable ions =>  solubility

Predicting Water Solubility
Empirical Approach Analytical Approach

Empirical Approach Lemke has developed an approach to predicting water solubility based upon the “solubilising potential” of various functional groups, versus the number of carbons Given that most drugs are polyfunctional, the second column is most relevant

Tareq Abu-Izneid Predicting Water Solubility 13/04/2017 The Empirical Approach – a working example Anileridine (Narcotic analgesic) We get a total “solubilising potential” of 9 carbons using this theory. Since the molecule contains 22 carbons, it suggests that the molecule is insoluble in water (USP has water solubility listed as <1g per 10,000ml) However, if we make the hydrochloride salt, then the compound becomes water soluble Lemke estimates that a charge (either anionic or cationic) contributes a “solubilising potential” of between 20 and 30 carbons Number of carbons in Foy’s page 46, (21 in Foy’s, it should be 22) Problem 6 in the end of this chapter provides more opportunity to predict water solubility of several compounds. PHM320-Topic-3-Drug Structure and Biological Activity

Tareq Abu-Izneid 13/04/2017 Predicting Water Solubility Analytical Approach The alternative approach for predicting water solubility utilises the “logP” of molecules Essentially, logP is a measure of lipophilicity (hydrophobic) properties of a molecule It is determined by measuring the “partition coefficient” between water and octanol for a given molecule (i.e. the solubility of the compound in octanol versus the solubility of the compound in water) Octanol is used as a mimic of the characteristics of a lipid membrane (polar at one end, long hydrocarbon chain at the other) LogP is calculated by adding the contributions from each functional group in the molecule A hydrophobic substituent constant π has been assigned to most organic functional groups, such that LogP = ∑ π (fragments) Page 47 in Foy’s See review of organic functional groups (Thomas L. Lemke) (CD examples, answers) PHM320-Topic-3-Drug Structure and Biological Activity

Predicting Water Solubility Analytical Approach-a working example
Tareq Abu-Izneid 13/04/2017 Predicting Water Solubility Analytical Approach-a working example Fragment π value Figure 2.14, page 48 in Foye’s Note that when dealing with esters and amide the oxygen, nitrogen and ester/amide carbon are counted in this (baay) Tertiary alkylamine and aromatic amine, 2 phenyl rings Aliphatic carbon 9 1 ester IMHB : intramolecular H-bonding, on (BAAY), would be expected to decrease water solubility (see Lemke page , Salicylic acid, with or without IMHB Water solubility is defined (by the USP) as greater than 3.3%, or a logP <+ 0.5 Therefore, anileridine, with a logP greater than is considered insoluble The “ionisation state” of a molecule not only influences water solubility, but also its ability to cross biological barriers or be absorbed See Fig. 2.15, page 38, Foye’s. PHM320-Topic-3-Drug Structure and Biological Activity

Stereochemistry and Biological Activity

Stereochemistry and Biological Activity
Tareq Abu-Izneid 13/04/2017 Stereochemistry and Biological Activity The physicochemical properties of a drug are not only influenced by which functional groups are present, but also by the spatial arrangement of groups. The spatial arrangement of groups is especially important when dealing with biological systems, since receptors are susceptible to the shape of a molecule. Stereoisomers contain the same number and kinds of atoms, the same arrangement of bonds, but a different spatial arrangement of atoms. A carbon atom with four different substituents is an asymmetric molecules. Stereochemistry is primary: Optical isomerism (Enantiomers, Diastereomers) Geometric isomerism Conformational isomerism If the crucial functional groups do not occupy the proper spatial region, so the desired pharmacological effect will not be possible However, if these functional groups are in the proper three dimensional orientation the drug can produce a strong interaction with the receptor So, it is very important for the medicinal chemist whose is responsible for developing new drug entity to understand not only the functional group are required for the molecule to bind, but also their spatial arrangement PHM320-Topic-3-Drug Structure and Biological Activity

Designation of stereoisomerism
Cahn, Ingold & Prelog (1956) devised a system of nomenclature for stereoisomer Prioritise atoms around a chiral centre, based upon the atomic weight of the atom Once you have assigned priority from 1 (= highest) to 4 (= lowest), then “look from the chiral centre towards the lowest priority and count from 1 to 3 If you count clockwise it is “R” If you count anticlockwise it is “S”

Optical Isomers & Biological Activity
Whilst enantiomers have identical physical properties, they can have very different biological properties (e.g. (+)-asparagine is sweet, whilst (–)-aspargine is tasteless). This was one of the earliest observation by in 1886). Easson-Stedman hypothesis states that the more potent enantiomer must be involved in a minimum of three interactions with the receptor and that the less potent enantiomer only interacts with two sites This difference is due to the asymmetry of receptor – ligand interactions

Selective Reactivity - Enantiomers
Tareq Abu-Izneid 13/04/2017 Selective Reactivity - Enantiomers R-(-)-epinephrine vs. S-(+)-epinephrine each enantiomer maps to the receptor site differently – (see Foye, Fig 2.19, page 41) Three interactions in the case of the (R epinphrine vs. two for the S) The three interactions are: protonated secondary ammonium, B-hydroxyl and the aromatic ring PHM320-Topic-3-Drug Structure and Biological Activity

Diastereomers – Asymmetric Centres
Stereoisomers with the same number and kinds of atoms, but in a different spatial arrangement (any stereoisomers compound that is not an enantiomer) These compounds have different physical and chemical properties These arise from compounds possessing two or more asymmetric centres Consider isomethadol 2 asymmetric carbons 4 isomers (2 pairs of enantiomers) only the (3S,5S)-isomer has analgesic activity.

Diasteroemers & Biological Activity
Most drugs contain more than one chiral centre, so therefore diastereomers become important. Two chiral centers: up to four stereoisomers, consists of two sets of enanatiomeric pairs. For each enantiomeric pair there is inversion of both chiral ecnters, while in the disteroemers there inversion in only one chiral center.

Enantiomeric Pair Differences
Some examples Isomethadol (cf methadone) - analgesic Acetylisomethadol - transformation induced Etomidate - nonbarbiturate hypnotic Ibuprofen - NSAID/Analgesic Naproxen - NSAID/Analgesic Verapamil - Ca channel blocker Warfarin - anticoagulant

Geometric isomers & biological activity
Geometrical isomerism (= restricted rotation) Sometimes E- and Z- becomes difficult to determine when it is less obvious which substituents are the highest priority: The key here is to assign the two groups on each side of the double bond, and then “simply” see if the two highest priority groups are on the same side or opposite sides Z- comes from German “Zusammen” (= together) E- comes from German “Entgegen” (= opposite)

Geometric isomers & biological activity
cis/trans isomers have different physical properties  distribution in biologic system varies generally leads to distinct biological activity But … difficult to correlate activity differences with stereochemistry alone eg different pKas of isomers => different levels of ionisation and hence => differing penetration or absorption

Cis-trans Spatial arrangement of pharmacophores
eg Diethylstilbestrol (W&L p62) trans isomer more active than cis trans-diethylstilbestrol cis-diethylstilbestrol

Conformational Isomers
Conformational isomerism - Eliel’s definition “ ... the no identical spatial arrangement of atoms in a molecule, resulting from rotation about one or more single bonds.” Involves both acyclic and cyclic drug molecules acyclic - flexible - Newman and sawhorse models cyclic - rigid - chair/boat model of conformers cyclic molecules of more interest medicinally

Conformational Isomers
Endogenous lead compounds often simple and flexible (e.g. adrenaline) Fit several targets due to different active conformations (e.g. adrenergic receptor types and subtypes) Rigidify molecule to limit conformations - conformational restraint Increases activity (more chance of desired active conformation) Increases selectivity (less chance of undesired active conformations) Disadvantage: Molecule more complex and may be more difficult to synthesise An Introduction to Medicinal Chemistry, Patrick, Third Edition

Conformational Isomers (Epinephrine)
RECEPTOR 2 RECEPTOR 1 An Introduction to Medicinal Chemistry, Patrick, Third Edition

INT116 Rotatable bonds Target inetraction site Tareq Abu-Izneid
13/04/2017 Rotatable bonds INT116 Target inetraction site An Introduction to Medicinal Chemistry, Patrick, Third Edition PHM320-Topic-3-Drug Structure and Biological Activity

INT116 Rotatable bonds Target interaction site Tareq Abu-Izneid
13/04/2017 Rotatable bonds INT116 Target interaction site An Introduction to Medicinal Chemistry, Patrick, Third Edition PHM320-Topic-3-Drug Structure and Biological Activity

INT117 Rotatable bonds Target interaction site Tareq Abu-Izneid
13/04/2017 Rotatable bonds INT117 Target interaction site An Introduction to Medicinal Chemistry, Patrick, Third Edition PHM320-Topic-3-Drug Structure and Biological Activity

Rigidification Methods - Introduce rings
Bonds within ring systems are locked and cannot rotate freely An Introduction to Medicinal Chemistry, Patrick, Third Edition

Isosterism and Bioisosterism
Tareq Abu-Izneid 13/04/2017 Isosterism and Bioisosterism When a lead compound first discovered, it is often lacks of potency and pharmacokienetic properties These undesirable properties could be due to specific functional groups present in the molecule. The medicinal chemist therefore must modify the compound to reduce these undesirable features without loosing the desired biological activity. PHM320-Topic-3-Drug Structure and Biological Activity

Isosterism and Bioisosterism
Tareq Abu-Izneid 13/04/2017 Isosterism and Bioisosterism A poor “drug profile” includes issues such as bioavailability, unwanted side effects, inability to cross biological barriers, poor pharmacokinetics. These undesirable features could be due to specific functional groups in the molecule. Modify this molecule to reduce these undesirable features WITHOUT losing the desired biological activity with other groups having similar properties is known as ISOSTERIC or BIOISOSTERIC replacement. In 1919 Langmuir first developed the concept of isosterism to describe the similarities in physical properties among atoms (same number of valence electrons O and S). In 1925 Grimm developed his hydride displacement law (illustration of similar physical properties among closely related functional groups) Thus, NH2 is considered to be isosteric to OH, SH, CH3) When a lead compound first discovered, it is often lacks of potency and pharmacokienetic properties These undesirable properties could be due to specific functional groups present in the molecule. The medicinal chemist therefore must modify the compound to reduce these undesirable features without loosing the desired biological activity. PHM320-Topic-3-Drug Structure and Biological Activity

Grimm’s isosteres Descending diagonally from left to right in the table H atoms are added to maintain the same number of valence electrons for each group of atoms within a column. Each member of a vertical group is isoelectronic

Isosterism Initially this concept related to the notion that different functional groups have the same number of valence electrons NH2 and OH are considered to be isosteric to each other Both groups are able to participate in hydrogen bonding interactions However, NH2 is basic at physiological pH, which means that changing an OH to an NH2 would give the molecule a positive charge at physiological pH (& therefore very different pharmacokinetics) Some isosteric replacements do work well (e.g. replace benzene with pyridine), but it is difficult to generalise between different biological systems

Isosterism and Pharmacological Activity
(example) “isosteric replacement” replacement of functional groups, where the chemical group considered to be important for activity is replaced by a different chemical group which has the “same” properties These “isosteres” are important when considering issues such as water solubility, acidity / basicity, lipophilicity, etc, since sometimes compounds with excellent biological activity have a poor “drug profile”

Bio-isosterism Classical and non-classical
Tareq Abu-Izneid 13/04/2017 Bio-isosterism This process attempts to overcome the limitations of isosteric replacement by considering not just the similarity in chemical structure between functional groups, but to also look at the biological effects Friedman definition “bio-isosteres are functional groups or molecules that have chemical and physical similarities producing broadly similar biological properties” Burger definition: “bio-isosteres are compounds or groups that possess near equal molecular shape and volumes, and with exhibit similar physical properties such as hydrophobicity”. The key point is that the same pharmacological target is influenced by bioisosteres as agonist or antagoinist. There are two general types of “bio-isosteres” Classical and non-classical What may work as an isosteric replacement in one biological system(oer a given drug receptor) may not in another? Because of this it was necessary to introduce the term bio-isosterism Burger expanded: bio-isosterism are compounds or groups that possess near equal molecular shape and volumes, and with exhibit similar physical properties such as hydrophobicity. PHM320-Topic-3-Drug Structure and Biological Activity

Bio-isosterism… Classical
Tareq Abu-Izneid Bio-isosterism… Classical 13/04/2017 (Monovalent bio-isosteres) A common replacement is F instead of H (in the development of antineoplastic agent 5-fluorouracil from Uracil) van der Waal’s radii: F = 1.35Å; H = 1.2Å (therefore very similar steric demand) The only real difference is electronegativity Tetravalent bio-isosteres of -tocopherol: -tocopherol (when X= C14H29) was found to accumulate in heart tissue All bio-isosteric analogues (when X= NMe3, PMe3 Or SMe2) were found to produce similar biological activity What may work as an isosteric replacement in one biological system(oer a given drug receptor) may not in another? Because of this it was necessary to introduce the term bio-isosterism In animals many hormones, neurotransmitters, with very similar structure and biological activity can be classified as bio-isosteres. An example is insuline isolated from various mammalian species. May differ by several amino acids but still produce the same biological activity. X=C14H29 PHM320-Topic-3-Drug Structure and Biological Activity

Examples of Bio-isosteres (Classical)

Bioisosterism….Non-Classical
Replace a functional group with another group which retains the same biological activity Not necessarily the same valency Example: antipsychotics Pyrrole ring = bio-isostere for amide group Improved selectivity for D3 receptor over D2 receptor An Introduction to Medicinal Chemistry, Patrick, Third Edition

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