Structure- Activity Relationships (SAR)

Structure- Activity Relationships (SAR)
The field of medicinal chemistry has evolved from an emphasis on the synthesis, isolation, and characterization of drugs to an increased awareness of the biochemistry of disease states and the design of drugs for the prevention of diseases. An important aspect of medicinal chemistry has been to establish a relationship between chemical structure and biological activity. An increased consideration in recent years has been to correlate the chemical structure with chemical reactivity or physical properties and these correlations can, in turn, be related to their therapeutic properties.

Although there has been a great deal of success in understanding the relationship between chemical structure and biological activity in a number of areas, especially for antibacterial drugs, there are still many human afflictions that require new and improved drugs. Cancer, viral infections, cardiovascular diseases, and mental diseases need new agents and approaches for treating and preventing these illnesses. Most drugs act at a specific site such as an enzyme or receptor. Compounds with similar structures often tend to have similar pharmacological activity. However, they usually exhibit difference in potency and unwanted side effects and in some cases different activities. These structurally related differences are commonly referred to as Structure- Activity Relationships (SAR)

A study of the Structure- Activity Relationships (SAR) of a lead compound (the original pharmacologically active compound from which these synthetic analogues are developed is known as lead compound) and it’s analogues can be used to determine the parts of the structure of the lead that are responsible for it’s biological activity, that is, it’s pharmacophore and also it’s unwanted side effects. This information is subsequently used to develop a new drug that has increased activity (optimize it’s SAR), a different activity from an existing drug, fewer unwanted side effects and Improved ease of administration to the patient.

Structure- Activity Relationships are usually determined by making minor changes to the structure of the lead and assessing the effect that this has on biological activity. Traditional SAR investigations are carried out by making large numbers of analogues of the lead and testing them for biological activity. Over the years numerous lead compounds have been investigated and from the mass of data it is possible to make some broad generalizations about biological effects of specific structural changes. These changes may be conveniently classified as: 1. the size and shape of the carbon skeleton, 2. the nature and degree of substitution, and 3. the stereochemistry of the lead. The selection of the changes required to produce analogues of a particular lead is made by considering the activities of compounds with similar structures and also the possible chemistry and biochemistry of the intended analogue.

For example, replacing a hydroxyl group with a methyl group could reduce the water solubility of the analogue and it’s ability to form hydrogen bonding. The former could reduce it’s ease of absorption whereas the latter could affect it’s ability to bind to it’s target site. It could improve the transport of the drug through membranes and also introduce changes in the metabolism of the drug. For example, oxidation of the methyl group to a carboxylic group could increase the rate of metabolism. All these effects could result in loss of activity or a reduction in unwanted side effects. A further consideration is the size of the analogue. Changing the structure of the lead could result in an analogue that is too big to fit it’s intended target site. Computerized molecular modeling can be used to check this provided that the structure of the target is known or can be simulated with some degree of accuracy. Traditional SAR investigation procedures are useful tools in the search for new drugs. However, they are expensive in both personnel and materials. Consequently, a number of attempts have been made to improve on traditional Structure- Activity investigations with varying degree of success.

Changing size and shape The shapes and sizes of molecules can be modified in a variety of ways, such as: 1. Changing the number of methylene groups in chains and rings; 2. ↑ or ↓ the degree of unsaturation: 3. Introducing or removing a ring system.

Changing the Number of Methylene Groups in a Chain Increasing the number of methylene groups in a chain or ring increases the size and the lipid nature (lipophilicity) of the compound. The biological response curves associated with this increase in size can assume a variety of shapes.(Fig.a). It is believed that the increase in activity with increase in number of methylene groups is probably due to an increase in lipid solubility of the analogue, which gives a better membrane penetration. Conversely, a decrease in activity (Fig.b) with an increase in number of methylene groups is attributed to a reduction in water solubility of the analogues. This reduction in water solubility can result in the poor distribution of the analogue in the aqueous media as well as the trapping of the analogue in the biological membranes A further problem with large increase in the umber of inserted methylene groups in a chain structure is micelle formation. Micelle formation produces large aggregates that, because of their shape, cannot bind to active sites and receptors.

Structure- Activity Relationships (SAR) Changing size and shape Changing the Number of Methylene Groups in a Chain

Structure- Activity Relationships (SAR) Changing size and shape
Introducing chain branching, different sized rings and the substitution of chains for rings and vice versa may also have an effect on the potency and type of activity of analogues. For example, the replacement of the sulphur atom of the antipsychotic chlorpromazine by CH2-CH2- produces the antidepressant clomipramine.

Structure- Activity Relationships (SAR) Changing size and shape Changing the Number of Methylene Groups in a Chain

Changing the Degree of Unsaturation The removal of double bonds increases the degree of flexibility of the molecule, which may make it easier for the analogue to fit into active and receptor sites by making up a more suitable conformation. However , an increase in flexibility could also result in a change or loss of activity. The introduction of the double bond increases the rigidity of the structure. It may also introduce the complication of E- and Z-isomers, which could have quite different activities. The analogues produced by the introduction of unsaturated structures into a lead compound may exhibit different degree of potency or different type of activities. For example, the potency of prednisone is about 30 times greater than that of it’s parent cortisol, which does not have a 1-2 C=C bond. The replacement of S atom of the antipsychotic phenothiazine drugs by a –CH=CH- group gives the antidepressant dibenzazepine drugs, such as protriptyline. The introduction of a C=C group will often give analogues that are more sensitive to metabolic oxidation. This may or may not be desirable feature for the new drug. Furthermore, the reactivity of C=C frequently causes the analogue to be more toxic than the lead.

Structure- Activity Relationships (SAR) Changing size and shape Changing the Degree of Unsaturation

Introduction or Removal of a Ring System The introduction of a ring system changes the shape and increases the overall size of the analogue. The effect of these changes on the potency and activity of the analogue is not generally predictable. However, the increase in size can be useful in filling a hydrophobic pocket in target site, which might strengthen the binding of the drug to the target. For example, it has been postulated that the increased inhibitory activity of the cyclopentyl analogue (rolipram) of 3-(3,4-dimethoxyphenyl)-butyrolactam towards cAMP phosphodiesterase is due to the cyclopentyl group filling a hydrophobic pocket in the active site of the enzyme.

Structure- Activity Relationships (SAR) Changing size and shape Introduction or Removal of a Ring System

Structure- Activity Relationships (SAR) Changing size and shape Introduction or Removal of a Ring System The incorporation of smaller, as against larger, alicyclic ring systems into a lead structure reduces the possibility of producing an analogue that is too big for it’s target site. It also reduces the possibility of complications caused by the existence of conformers. However, the selection of the system for a particular analogue may depend on the objective of the alteration. For example, the cyclopropane ring is usually more stable than the ethylenic C=C and so could be used to replace this group if a more stable compound of a similar size is required. For example the antidepressant tranylcypromine is more stable than it’s analogue1-amino-2-phenylethene.

Introduction or Removal of a Ring System The insertion of aromatic system into the structure of the lead will introduce rigidity into the structure as well as increase the size of the analogue. The latter means that small aromatic systems such as benzene and five membered heterocyclic systems are preferred to larger systems. However, the π electrons of aromatic systems may or may not improve the binding of the analogue to it’s target site. Furthermore, heterocyclic aromatic systems will also introduce extra functional groups into the structure, which could also affect the potency and activity of the analogue. For example, the replacement of N-dimethyl group of chlorpromazine by an N-methylpiperazine group produces an analogue (prochlorperazine) with increased antiemetic potency but reduced neuroleptic activity. It has been suggested that this change in activity could be due to the presence of extra tertiary-amine group

Structure- Activity Relationships (SAR) Changing size and shape Introduction or Removal of Ring System

Introduction or Removal of a Ring System The incorporation of a ring systems, especially larger systems into a structure of a lead can be used to produce analogues that are resistant to enzymatic attack by sterically hindering the access of the enzyme to the relevant functional group. For example, the resistance of diphenicillin to ß-lactamse is believed to be due to the diphenyl group preventing the enzyme from reaching the ß-lactam. It is interesting to note that 2-phenylbenzylpenicillin is not resistant to ß-lactamase attack. In this case, it appears that the diphenyl group is too far away from the ß-lactam ring to hinder the attack of the ß-lactamase.

Structure- Activity Relationships (SAR) Changing size and shape Introduction or Removal of Ring System

Introduction or Removal of a Ring System Many of the potent pharmacologically active naturally occurring compounds, such as the alkaloid morphine and curare, have such complex structures that it would not be economical to synthesize them on large scale. Furthermore, they also tend to exhibit unwanted side effects. However, the structures of many of these compounds contain several ring systems. In these cases, one approach to designing analogues of these compounds centres around determining the pharmacophore and removing any surplus ring structures. It is hoped that this will also result in the loss of any unwanted side effects.

Structure- Activity Relationships (SAR) Introduction of New Substituents
The formation of analogue by introduction of new substituents into the structure of a lead may result in an analogue with significantly different chemical and hence pharmacokinetic properties. For example, the introduction of a new substituent may cause significant changes in lipophilicity that affect transport of the analogue through membranes and the various fluids found in the body. It would also change the shape, which could result in conformational restrictions that affect the binding to the target site. In addition, the presence of a new group may introduce a new metabolic pathway for the analogue. These changes will in turn affect the pharmacodynamic properties of the analogue. For example, they could result in an analogue with either increased or decreased potency, duration of action, metabolic stability and unwanted side effects. Each substituent will impart it’s own characteristic properties to the analogue. However, it is possible to generalize about the effect of introducing a new substituent group into a structure but there will be numerous exceptions to the predictions.

Methyl Groups. The introduction of methyl groups increases the lipophilicity of the compound and reduces it’s water solubility. It should improve the ease of absorption of the analogue into a biological membrane but will make it’s release from biological membranes into the aqueous media more difficult. P values for Toluene, 490, Propionamide 360, N-methlurea 44.

Methyl Groups The incorporation of a methyl group can impose steric restrictions on the structure of an analogue. For example, the ortho-methyl analogue of diphenhydramine exhibits no antihistaminic activity. Harmes and colleagues suggest that this could be due to the ortho-methyl restricting rotation about C-O bond of the side chain. This prevents the molecule from adopting the conformation necessary for antihistaminic activity. It is interesting to note that the para-methyl analogue is 3.7 times more active than diphenhydramine

Methyl Groups The incorporation of a methyl group can have one of three general effects on the rate of metabolism of a analogue: an ↑ rate of metabolism due to oxidation of methyl group; an ↑ in rate of metabolism due to demethylation by the transfer of methyl group to another compound; or a ↓ in the rate of metabolism of the analogue.

Methyl Groups i) A methyl group bound to an aromatic ring or a structure which increases it’s reactivity may be metabolized to a carboxylic acid, which can be eliminated more easily. For example , the antidiabetic tolbutamide is metabolized to it’s less toxic benzoic acid derivative.

Methyl Groups (ii) Demethylation is more likely to occur when the methyl group is attached to positively charged nitrogen and sulphur atoms, although it is possible for any methyl group attached to nitrogen, oxygen or sulphur atom to act in this manner. A number of methyl transfers have been associated with carcinogenic action. (iii) Methyl groups can reduce the rate of metabolism of a compound by masking a metabolically active group, thereby giving the analogue a slower rate of metabolism than the lead. For example the action of the agricultural fungicide nabamis due to it being metabolised to the deactive diisothiocyanate. N-Methylation of nabam yeilds and analogue that is inactive because it cannot be metabolised to the diisothiocyanate.

Methyl Groups

Methyl Groups Methylation can also reduce the unwanted side affects of a drug. For example, mono and di ortho-methylation with respect to the phenolic hydroxy group of paracetamol produce analogues with reduced hepatotoxity. It is believed that this reduction is due to the methyl groups preventing metabolic hydroxylation of these ortho positions.

Halogen Groups The incorporation of halogen atoms into lead results in analogues that are more lipophilic and so less water soluble. Consequently, halogen atoms are used to improve the penetration of lipid membranes. However, there is an undesirable tendency for halogenated drugs to accumulate in the lipid tissues. The chemical reactivity of halogen atoms depends on both their point of attachment to the lead and the nature of the halogen. Aromatic halogen groups are far less reactive than aliphatic halogen groups, which can exhibit considerable chemical reactivity. For aliphatic carbon-halogen bonds C-F bond is the strongest and usually less chemically reactive than aliphatic C-H bonds.

Halogen Groups The other aliphatic C-halogen bonds are weaker, their reactivity increases down the periodic table.They are usually more chemically reactive than aliphatic C-H bonds. Consequently, the most popular halogen substitutions are the less reactive aromatic fluorine and chlorine groups. However, the presence of electron-withdrawing ring substituents may increase their reactivity to unacceptable level. Trifluorocarbon groups (-CF3) are sometimes used to replace chlorine because these groups are of a similar size. These substitutions avoid introducing a very reactive centre and hence possible site for unwanted side reactions into the analogue. For example, the introduction of the more reactive bromo group can cause the drug to act as an alkylating agent.

Halogen Groups The changes in potency caused by the introduction of a halogen or halogen-containing groups will, as with substitution by other substituents, depends on the position of the substitution. For example, the antihypertensive clonidine with its o,o`-chloro substitution is more potent than its p,m-dichloro analogue. It is believed that the bulky ortho chlorine groups impose a conformation restriction on the structure of Clonidine, which probably accounts for its increased activity.

Hydroxy Groups The introduction of hydroxy groups into the structure of lead will normally produce analogues with increased hydrophilic nature and a lower lipid solubility. It also provides a new centre for hydrogen bonding which could influence the binding of the analogue to its target site. For example, the orthohydroxylated minaprine analogue binds more effectively to M1- muscarinic receptors than many of its non-hydroxylated analogues. The introduction of hydroxy group also introduces a centre that, in the case of phenolic groups, could act as a bacteriocide whereas alcohols have narcotic properties. However, the presence of hydroxy groups opens a new metabolic pathway that can either act as a detoxification route or prevent the drugs from reaching its target.

Basic Groups The basic groups usually found in drugs are amines, including some ring nitrogen atoms, amidines and guanidines. All these basic groups can form salts in biological media. Consequently, incorporation of these basic groups into the structure of lead will produce analogues that have a lower lipophilicity but an increased water solubility. This means that the more basic an analogue, the more likely it will form salts and the less likely it will be transported through a lipid membrane.

Basic Groups The introduction of basic group may increase the binding of an analogue to its target by hydrogen bonding between that target and the basic group. (as in Fig.a). However, a number of drugs with basic groups owe their activity to salt formation and the enhanced binding that occurs due to the ionic bonding between the drug and the target. (as in Fig.b). For example, it is believed that many local anaesthetics are transported to their site of action in the form of their free bases but are converted to their salts which bind to the appropriate receptor sites. The incorporation of aromatic amines into the structure of a lead is usually avoided because aromatic amines are often very toxic and carcinogenic.

Carboxylic and Sulphonic Acid Groups The introduction of acid groups into the structure of a lead usually results in analogues with an increased water but reduced lipid solubility. This increase in water solubility may be enhanced subsequently by in vivo salt formation. In general the introduction of carboxylic and sulphonic acid groups into a lead produces analogues that can be eliminated more readily. The introduction of carboxylic acid groups into small lead molecules may produce analogues that have a different type of activity or are inactive. For example, the introduction of carboxylic acid group into phenol results in the activity of the compound changing from being a toxic antiseptic to the less toxic anti-inflammatory salicylic acid. Similarly, the incorporation of carboxylic acid group into the sympathomimetic phenylethylamine gives phenylalanine which has no sympathomimetic activity.

Carboxylic and Sulphonic Acid Groups However, the introduction of carboxylic acid groups appears to have less effect on the activity of large molecules. Sulphonic acid groups do not usually have any effect on the biological activity but will increase the rate of elimination of an analogue.

Thiols, Sulphides and other Sulphur Groups. Thiols and sulphide groups are not usually introduced into leads in SAR studies because they are readily metabolized by oxidation. However, thiols are sometimes introduced into a lead structure when improved metal chelation is the objective of the SAR studies. For example, the antihypertensive captopril was developed from the weakly active carboxyacylprolines by replacement of their terminal carboxylic acid group (which is only a weak ligand for forming complexes with metals) by a thiol group. The introduction of thiourea and thiamide groups is usually avoided because these groups may produce goiter.

Structure- Activity Relationships (SAR) Changing the Existing Substituent of a Lead
Analogues can also be formed by replacing an existing substituent in the structure of lead by a new substituent group.The choice of group will depend on the objectives of design team. It is often made using the concept of Isosteres. Isosteres are groups that exhibit some similarities in their chemical and/or physical properties. As a result, they can exhibit similar pharmacokinetic and pharmacodynamic properties. In other words, the replacement of a substituent by it’s isostere is most likely to result in the formation of an analogue with the same type of activity as the lead than the totally random selection of an alternative substituents. However, luck still plays a part and an isosteric analogue may have a totally different type of activity from it’s lead. Classical isosteres were originally defined by Erlenmeyer as being atoms, ions and molecules that had identical outer shells of electrons. This definition has now been broadened to include groups that produce compounds that can sometimes have similar biological activities (bioisosteres).

Structure- Activity Relationships (SAR) Changing the Existing Substituent of a Lead Examples of bioisosteres

Structure- Activity Relationships (SAR) Changing the Existing Substituent of a Lead
A large number of drugs have been discovered by isosteric and bioisosteric interchanges. For example, the replacement of the 6-hydroxy group of hypoxanthine by thiol group gave the antitumour drug 6-mercaptopurine whereas the replacement of hydrogen in the 5 position of uracil by fluorine resulted in fluouracil, which is also an antitumour agent. However, not all isosteric changes yield compounds with the same type of activity: the replacement of the -S- of the neuroleptic phenothiazine drugs by either -CH=CH- or -CH2-CH2- produces the dibenzazepines, which exhibit antidepressant activity.

Structure- Activity Relationships (SAR) Changing the Existing Substituent of a Lead Examples of drugs discovered by isosteric replacement

Structure- Activity Relationships (SAR)

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Structure- Activity Relationships (SAR)

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