Presentation is loading. Please wait.

Presentation is loading. Please wait.

1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 22 ANTIULCER AGENTS Part 1: Histamine antagonists.

Similar presentations


Presentation on theme: "1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 22 ANTIULCER AGENTS Part 1: Histamine antagonists."— Presentation transcript:

1 1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 22 ANTIULCER AGENTS Part 1: Histamine antagonists

2 1 © Contents 1.Introduction 1.1.Ulcers 1.2.Therapy of ulcers 1.3.Parietal cells and gastric acid release 2.Histamine 2.1.Properties 2.2.Actions 3.Classical Antihistamines 4.Histamine as a Lead Compound 5.SAR for H1 and H2 Agonists 6.Strategies for converting Agonists to Antagonists (3 slides) 7.Na-Guanylhistamine 7.1.Biological properties 7.2.Structure and chemical properties continued… 8.Binding Theory for Agonists and Antagonists 8.1.Binding regions 8.2.Binding of histamine 8.3.Binding of Na- guanylhistamine 9.Chelation Binding Theory 9.1.The proposal 9.2.The evidence 9.3.Binding modes for analogues 10.Chain Extension Strategy 10.1.Aim 10.2.Results 10.3.Proposed binding for 3C extension analogues (2 slides) 10.4.Further evidence (2 slides)

3 1 © continued… 11.Distinguishing between the Polar Binding Regions 11.1.Strategy 11.2.Rationale 11.3.Method 11.4.SK&F Comparison between the thiourea and guanidine groups 12.Chain Extension (2 slides) 13.The Imidazole Ring 13.1.Structures 13.2.Basicity 13.3.Varying basicity 13.4.Tautomer studies (2 slides) 14.Alternative Rationales (2 slides) 15.From Metiamide to Cimetidine (3 slides) 16.Cimetidine (Tagamet) 16.1.Properties 16.2.The cyanoguanidine moietycontinued… 16.3.The cyanoguanidine moiety - tautomers 16.4.The cyanoguanidine moiety - conformational isomers 16.5.The cyanoguanidine moiety - binding mode 17.Analogues 17.1.The urea analogue 17.2.Rigid nitropyrrole analogue 18.Desolvation Theory 18.1.The process 18.2.Hydrophobic analogues (3 slides) 19.Dipole Moment Theory 19.1.Proposal 19.2.Dipole-dipole interactions 19.3.QSAR study including dipole-dipole interactions 20.Ranitidine (Zantac) [53 slides]

4 1 © 1. Introduction 1.1 Ulcers Localised erosions of the mucous membranes of the stomach and duodenumLocalised erosions of the mucous membranes of the stomach and duodenum Potentially fatal if untreatedPotentially fatal if untreated Caused by stress, infection (H. Pylori) and drugs (NSAIDS)Caused by stress, infection (H. Pylori) and drugs (NSAIDS) Aggrevated by gastric acid (HCl) in the stomachAggrevated by gastric acid (HCl) in the stomach 1.2 Therapy of ulcers Lower the levels of gastric acidLower the levels of gastric acid - histamine antagonists and proton pump inhibitors Antibacterial agents vs. H. PyloriAntibacterial agents vs. H. Pylori Herbal remediesHerbal remedies

5 1 © Antrum Stomach Pyloric Sphincter oesophagus Duodenum Histamine Acetylcholine Gastrin Cck 2 M3M3 H2H2 Parietal Cells Stomach 1. Introduction 1.3 Parietal cells and gastric acid release Proton pump Receptors Ion channel Release of gastric acid is promoted by acetylcholine, gastrin and histamineRelease of gastric acid is promoted by acetylcholine, gastrin and histamine cAMP H HCl Cl

6 1 © 2. Histamine 2.1 Properties A chemical messenger released by cellsA chemical messenger released by cells Acts as a local hormoneActs as a local hormone Two possible tautomersTwo possible tautomers pK a for the  -NH 2 group = 9.80.pK a for the  -NH 2 group = % ionisation at pH 7.4 = 99.6% ionisation at pH 7.4 = 99.6 pK a for the imidazole ring = 5.74pK a for the imidazole ring = 5.74 Imidazole ring is not ionised at blood pHImidazole ring is not ionised at blood pH

7 1 © 2. Histamine Histamine is released by cell damage Also released by allergies, asthma, hay fever and insect bites BUT Stimulates dilation of blood vessels with increased permeability White blood cells escape blood vessels and access area of tissue damage White blood cells combat infection 2.2 Actions

8 1 © Commonly used to treat symptoms such as inflammation & itching But no effect on gastric acid releaseBut no effect on gastric acid release Casts doubt on histamine receptors being present on parietal cellsCasts doubt on histamine receptors being present on parietal cells Histamine may promote gastric acid release indirectlyHistamine may promote gastric acid release indirectly SK&F propose two types of histamine receptor (H 1 and H 2 )SK&F propose two types of histamine receptor (H 1 and H 2 ) H 1 - responsible for classical actions of histamineH 1 - responsible for classical actions of histamine H 2 - proposed as the receptor on the parietal cellsH 2 - proposed as the receptor on the parietal cells Claim that H 2 receptors are unaffected by classical antihistaminesClaim that H 2 receptors are unaffected by classical antihistamines Implies classical antihistamines are H 1 specificImplies classical antihistamines are H 1 specific 3. Classical Antihistamines

9 1 © No known H 2 antagonist at the time - no lead compoundNo known H 2 antagonist at the time - no lead compound SK&F decide to use histamine itself as the lead compoundSK&F decide to use histamine itself as the lead compound Aim is to alter an agonist into an antagonistAim is to alter an agonist into an antagonist Compare development of propranolol (  -blocker) from adrenalineCompare development of propranolol (  -blocker) from adrenaline Need to know SAR requirements for H 2 agonistsNeed to know SAR requirements for H 2 agonists Analogues tested by their ability to promote gastric acid releaseAnalogues tested by their ability to promote gastric acid release Does not prove existence of H 2 receptorDoes not prove existence of H 2 receptor 4. Histamine as a Lead Compound

10 1 © Two nitrogen atoms are required for H 1 agonist activityTwo nitrogen atoms are required for H 1 agonist activity All three nitrogen atoms are required for H 2 agonist activityAll three nitrogen atoms are required for H 2 agonist activity 5. SAR for H 1 and H 2 Agonists H1 Receptor H2 Receptor

11 1 © Add extra functional groups to find extra binding interactions with the binding siteAdd extra functional groups to find extra binding interactions with the binding site Extra binding interactions may result in a different mode of binding resulting in a different induced fit for the receptorExtra binding interactions may result in a different mode of binding resulting in a different induced fit for the receptor Different induced fit may fail to activate the receptorDifferent induced fit may fail to activate the receptor A a result, analogue binds but fails to activate the receptorA a result, analogue binds but fails to activate the receptor Analogue likely to bind more strongly than an agonistAnalogue likely to bind more strongly than an agonist 6. Strategies for converting Agonists to Antagonists

12 1 © Receptor (Inactive) Histamine Extra Functionality Induced Fit - Receptor 'Switched on' Receptor (Inactive) 6. Strategies for converting Agonists to Antagonists Different induced fit

13 1 © Examples - extra hydrophobic groups Results No antagonist activity observed with extra hydrophobic groupsNo antagonist activity observed with extra hydrophobic groups Try adding extra hydrophilic groups insteadTry adding extra hydrophilic groups instead Aim is to search for extra polar binding regionsAim is to search for extra polar binding regions 6. Strategies for converting Agonists to Antagonists

14 1 © 7. N a -Guanylhistamine 7.1 Biological properties Partial agonist - promotes HCl release but less strongly than histaminePartial agonist - promotes HCl release but less strongly than histamine Prevents histamine from fully promoting the release of HClPrevents histamine from fully promoting the release of HCl SK&F suggest that N   guanylhistamine is binding to the proposed H 2 receptor, resulting in weak activationSK&F suggest that N   guanylhistamine is binding to the proposed H 2 receptor, resulting in weak activation Whilst present, N   guanylhistamine blocks histamine from binding Whilst present, N   guanylhistamine blocks histamine from binding Guanidine moiety

15 1 © The guanidine group is basic and ionisedThe guanidine group is basic and ionised Different tautomers are possibleDifferent tautomers are possible The positive charge can be delocalisedThe positive charge can be delocalised The positive charge is more diffuse and can be further away from the imidazole ring 7. N a -Guanylhistamine 7.2 Structure and chemical properties

16 1 © Three binding regions are proposed for the H 2 receptor - an imidazole binding region and two polar binding regionsThree binding regions are proposed for the H 2 receptor - an imidazole binding region and two polar binding regions Two binding modes are proposed - one for agonists and one for antagonistsTwo binding modes are proposed - one for agonists and one for antagonists The imidazole binding region is common to both binding modesThe imidazole binding region is common to both binding modes One of the polar binding regions is accessed by agonists and the other by antagonistsOne of the polar binding regions is accessed by agonists and the other by antagonists The antagonist polar region is further from the imidazole binding regionThe antagonist polar region is further from the imidazole binding region 8. Binding Theory for Agonists and Antagonists 8.1 Binding regions Antagonist binding region Agonist binding region Imidazole ring binding region

17 1 © Antagonist binding region Agonist binding region Imidazole ring binding region Antagonist binding region Histamine has a short chainHistamine has a short chain Charged  -nitrogen can only reach the polar agonist regionCharged  -nitrogen can only reach the polar agonist region The antagonist binding region is out of rangeThe antagonist binding region is out of range Histamine can only bind as an agonistHistamine can only bind as an agonist Histamine acts as a pure agonistHistamine acts as a pure agonist 8. Binding Theory for Agonists and Antagonists 8.2 Binding of histamine No interaction as an antagonist Strong interaction as an agonist

18 1 © Binding as an antagonist Receptor not activated Binding as an agonist Receptor activated Positive charge on the structure is more diffuse and further outPositive charge on the structure is more diffuse and further out Allows N  -guanylhistamine to bind in two different modesAllows N  -guanylhistamine to bind in two different modes Structure binds as an agonist in one mode and as an antagonist in the other mode, making it a partial agonistStructure binds as an agonist in one mode and as an antagonist in the other mode, making it a partial agonist Agonist binding region Imidazole ring binding region Antagonist binding region 8. Binding Theory for Agonists and Antagonists 8.3 Binding of N  -guanylhistamine

19 1 © SK&F propose that the guanidine moiety interacts with a carboxylate ion in the antagonist binding region by means of two H-bonds and an ionic interaction 9. Chelation Binding Theory 9.1 The proposal Receptor X=NH,S Strong interaction 9.2 The evidence X= SMe, Me B A Structures A and B are both partial agonists, but structure A has greater antagonist properties

20 1 © Receptor X=Me, SMe Weak interaction Receptor Strong interaction Positive charge is localised further out leading to better interactions with the antagonist binding region Only one H-bond is possible with the antagonist binding region. Charge is also directed away from the carboxylate ion - weaker antagonist property. 9. Chelation Binding Theory 9.3 Binding modes for analogues The chelation binding theory was eventually disproved but it served a purpose in explaining results and pushing the project forward on rational groundsThe chelation binding theory was eventually disproved but it served a purpose in explaining results and pushing the project forward on rational grounds

21 1 © 10.1 Aim: To push the polar guanidine group further out and to increase the interaction with the antagonist binding region 10. Chain Extension Strategy Partial agonist Antagonist activity increases Partial agonist Antagonist activity decreases! 10.2 Results: Antagonist activity of the extended guanidine analogue increases as expectedAntagonist activity of the extended guanidine analogue increases as expected Isothiourea analogue might have been expected to have increased antagonist activity since the charge is further outIsothiourea analogue might have been expected to have increased antagonist activity since the charge is further out 3C Bridge

22 1 © Receptor X=NH,S Strong interaction Compare 2C bridged analogues Receptor Strong interaction 10. Chain Extension Strategy 10.3 Proposed binding for 3C extension analogues Different form of hydrogen bonding taking placeDifferent form of hydrogen bonding taking place Receptor Weak interaction

23 1 © Good binding as an antagonist Binding as an agonist Antagonist binding region Agonist binding region Imidazole ring binding region 10. Chain Extension Strategy 10.3 Proposed binding for 3C extension analogues

24 1 © 10. Chain Extension Strategy 10.4 Further evidence Partial agonists with good antagonist activity (X= Me or SMe) Receptor X=NH 2, SMe, Me Strong interaction Binding mode

25 1 © Agonist binding region Agonist binding region Poor binding as an antagonist Good binding as an antagonist Emphasis now switches to the types of binding interactions at the polar binding regionsEmphasis now switches to the types of binding interactions at the polar binding regions 10. Chain Extension Strategy 10.4 Further evidence

26 1 © 11. Distinguishing between the Polar Binding Regions 11.1 Strategy: Replace the ionic guanidine group with a neutral H-bonding groupReplace the ionic guanidine group with a neutral H-bonding group 11.2 Rationale: May allow a distinction to be made between the two polar binding regions.May allow a distinction to be made between the two polar binding regions. Ionic bonding is known to be crucial for the agonist binding regionIonic bonding is known to be crucial for the agonist binding region It may not be crucial for the antagonist binding regionIt may not be crucial for the antagonist binding region 11.3 Method: Replace the basic guanidine moiety with a neutral thiourea groupReplace the basic guanidine moiety with a neutral thiourea group

27 1 © 11.4 SK&F Thiourea No agonist activity, very weak antagonist 11. Distinguishing between the Polar Binding Regions

28 1 © Similarities - Planarity, geometry, size, polarity, H-bonding ability Differences - Thiourea is neutral while guanidine is basic and ionised e-withdrawing ThioureaGuanidineNeutralBasic Conclusions - Agonist polar region involves ionic and H-bonding interactionsAgonist polar region involves ionic and H-bonding interactions Antagonist polar region may not require ionic interactions. H-bonding may be sufficientAntagonist polar region may not require ionic interactions. H-bonding may be sufficient 11.5 Comparison between the thiourea and guanidine groups 11. Distinguishing between the Polar Binding Regions

29 1 © Strategy Extend the carbon bridge to 4 carbonsExtend the carbon bridge to 4 carbons Pushes thiourea group further outPushes thiourea group further out May increase the interaction with the antagonist binding regionMay increase the interaction with the antagonist binding region 12. Chain Extension Results Discovery of burimamide

30 1 © Properties of burimamide Conclusions – Chain extension leads to a pure antagonist with good activityChain extension leads to a pure antagonist with good activity Chain extension allows a better overlap of the thiourea group with the antagonist binding regionChain extension allows a better overlap of the thiourea group with the antagonist binding region Establishes the existence of H 2 receptorsEstablishes the existence of H 2 receptors 100 times more active as an antagonist compared to N  - guanylhistamine100 times more active as an antagonist compared to N  - guanylhistamine No antagonist activity at H 1 receptorsNo antagonist activity at H 1 receptors Activity too low for oral useActivity too low for oral use 12. Chain Extension

31 1 © Imidazole ring can exist as two tautomers (I) and (II) as well as two ionised forms (III)Imidazole ring can exist as two tautomers (I) and (II) as well as two ionised forms (III) Which of these is preferred?Which of these is preferred? III III 13. The Imidazole Ring 13.1 Structures

32 1 © Imidazole pK a = 6.80 Histamine pK a = 5.74 Ionisation = 3% Burimamide pK a = 7.25 Ionisation = 40% Conclusions The imidazole ring of histamine is not ionised when it interacts with the imidazole binding regionThe imidazole ring of histamine is not ionised when it interacts with the imidazole binding region The ionised form of burimamide is unlikely to bind wellThe ionised form of burimamide is unlikely to bind well Decreasing the basicity and ionisation of the imidazole ring in burimamide closer to that of histamine may increase the binding interactions to the imidazole binding regionDecreasing the basicity and ionisation of the imidazole ring in burimamide closer to that of histamine may increase the binding interactions to the imidazole binding region e-withdrawing e-donating 13. The Imidazole Ring 13.2 Basicity

33 1 ©Strategy Convert the side chain of burimamide to an e-withdrawing group Thiaburimamide pK a = 6.25 Increase in antagonist activity Non-ionised imidazole is favoured 13. The Imidazole Ring 13.3 Varying basicity

34 1 © Tautomer I vs tautomer II Favoured tautomer for histamine is IFavoured tautomer for histamine is I Side chain is electron withdrawingSide chain is electron withdrawing Inductive effect decreases with distanceInductive effect decreases with distance N  is less basic than N N  is less basic than N  N  is more likely to be protonatedN  is more likely to be protonated Favoured tautomer for thiaburimamide is also tautomer IFavoured tautomer for thiaburimamide is also tautomer I Strategy Increase the basicity of N  relative to N  to further increase the percentage population of tautomer I vs tautomer IIIncrease the basicity of N  relative to N  to further increase the percentage population of tautomer I vs tautomer II Add an electron donating group to the imidazole ring closer to N  than to N Add an electron donating group to the imidazole ring closer to N  than to N  13. The Imidazole Ring 13.4 Tautomer studies Inductive effect

35 1 © Metiamide 10 fold increase in antagonist activity w.r.t burimamide10 fold increase in antagonist activity w.r.t burimamide Electron-donating effect of methyl group is more significant at N Electron-donating effect of methyl group is more significant at N  Increases basicity of N Increases basicity of N  Favours tautomer I over tautomer IIFavours tautomer I over tautomer II Increase in pK a to 6.80Increase in pK a to 6.80 Increase in ionisation to 20%Increase in ionisation to 20% Increase in the population of tautomer (I) outweighs the increase in population of the ionised structures (III)Increase in the population of tautomer (I) outweighs the increase in population of the ionised structures (III) Unacceptable side effects - kidney damageUnacceptable side effects - kidney damage Electron withdrawing 13. The Imidazole Ring 13.4 Tautomer studies

36 1 © The increases in activity for thiaburimamide and metiamide may be due to a conformational effectThe increases in activity for thiaburimamide and metiamide may be due to a conformational effect The thioether link increases the length and flexibility of the side chainThe thioether link increases the length and flexibility of the side chain This may lead to increased bindingThis may lead to increased binding The methyl substituent may orientate the side chain into the active conformation - i.e. the methyl group acts as a conformational blockerThe methyl substituent may orientate the side chain into the active conformation - i.e. the methyl group acts as a conformational blocker 14. Alternative Rationales

37 1 © Oxaburimamide Less potent than burimamide despite the side chain being electron withdrawingLess potent than burimamide despite the side chain being electron withdrawing Possible explanations The ether link is smaller and less flexibleThe ether link is smaller and less flexible The ether may be involved in a ‘bad’ hydrogen bondThe ether may be involved in a ‘bad’ hydrogen bond There may be an energy penalty involved in desolvating the oxygen prior to bindingThere may be an energy penalty involved in desolvating the oxygen prior to binding 14. Alternative Rationales

38 1 © The side effects of metiamide may be due to the thiourea groupThe side effects of metiamide may be due to the thiourea group The thiourea group is not a natural functional groupThe thiourea group is not a natural functional group Replacing thiourea with a natural functional group may remove the side effectsReplacing thiourea with a natural functional group may remove the side effects Thiourea Toxic side effects Guanidine Drop in activity but no agonist activity! Urea Drop in activity Conclusions First guanidine analogue to be a pure antagonistFirst guanidine analogue to be a pure antagonist The longer 4C chain pushes the guanidine unit beyond the agonist binding region, but not beyond the antagonist binding regionThe longer 4C chain pushes the guanidine unit beyond the agonist binding region, but not beyond the antagonist binding region 15. From Metiamide to Cimetidine

39 1 © Binding as an antagonist No binding as an agonist Agonist binding region 15. From Metiamide to Cimetidine Binding interactions for the 4C extended guanidine

40 1 © Strategy: Retain the guanidine groupRetain the guanidine group Guanidine is a natural group present in the amino acid arginineGuanidine is a natural group present in the amino acid arginine Increase activity by making the guanidine group neutralIncrease activity by making the guanidine group neutral Add a strong electron withdrawing group to decrease basicity (e.g. NO 2 or CN)Add a strong electron withdrawing group to decrease basicity (e.g. NO 2 or CN)Cimetidine 15. From Metiamide to Cimetidine Electron withdrawing cyanide group

41 1 © 16.1 Properties Comparable activity to metiamideComparable activity to metiamide Less side effectsLess side effects Inhibits H 2 -receptors and lowers levels of gastric acid releasedInhibits H 2 -receptors and lowers levels of gastric acid released Marketed in 1976Marketed in 1976 Biggest selling prescription drug until ranitidineBiggest selling prescription drug until ranitidine Metabolically stableMetabolically stable Inhibits cytochrome p450 enzymesInhibits cytochrome p450 enzymes Drug-drug interactions with diazepam, lidocaine and warfarinDrug-drug interactions with diazepam, lidocaine and warfarin 16. Cimetidine (Tagamet)

42 1 © 16.2 The cyanoguanidine moiety 16. Cimetidine (Tagamet) Both groups are planar and of similar geometryBoth groups are planar and of similar geometry Both groups are polar but essentially neutralBoth groups are polar but essentially neutral Both groups have high dipole momentsBoth groups have high dipole moments Both groups have low partition coefficientsBoth groups have low partition coefficients The cyanoguanidine group is weakly acidic and weakly basic - amphotericThe cyanoguanidine group is weakly acidic and weakly basic - amphoteric The cyanogaunidine group is not ionised at pH 7.4The cyanogaunidine group is not ionised at pH 7.4 Acts as a bio-isostere for the thiourea groupActs as a bio-isostere for the thiourea group

43 1 © The favoured tautomer is the imino tautomerThe favoured tautomer is the imino tautomer 16. Cimetidine (Tagamet) 16.3 The cyanoguanidine moiety - tautomers The electron withdrawing effect of the CN group is an inductive effectThe electron withdrawing effect of the CN group is an inductive effect The inductive effect is felt most at the neighbouring nitrogenThe inductive effect is felt most at the neighbouring nitrogen The neighbouring nitrogen is least likely to form a bond to hydrogenThe neighbouring nitrogen is least likely to form a bond to hydrogen

44 1 © The E, E and Z,Z conformations are not favoured - X-ray and nmr evidenceThe E, E and Z,Z conformations are not favoured - X-ray and nmr evidence Bad news for the chelation bonding theoryBad news for the chelation bonding theory Chelation to the one carboxylate group requires the E,E or the Z,Z conformationChelation to the one carboxylate group requires the E,E or the Z,Z conformation Stericinteraction Stericinteraction 16. Cimetidine (Tagamet) 16.4 The cyanoguanidine moiety - conformational isomers

45 1 © Receptor Two H-bonds are not possible for the favoured conformations E,Z Receptor Two separate H-bonds to 2 different H-bond acceptors are more likely 16. Cimetidine (Tagamet) 16.5 The cyanoguanidine moiety - binding mode

46 1 © 17.1 The urea analogue The preferred conformation for the urea analogue is E,E or Z,ZThe preferred conformation for the urea analogue is E,E or Z,Z Weak antagonistWeak antagonist Unable to bind to two different binding groups in the antagonist binding regionUnable to bind to two different binding groups in the antagonist binding region 17. Analogues

47 1 © 17.2 Rigid nitropyrrole analogue Unable to adopt the E,E or Z,Z conformationUnable to adopt the E,E or Z,Z conformation Strongest analogue of cimetidineStrongest analogue of cimetidine Locked into the active conformationLocked into the active conformation Can only interact with two separate H-bond acceptors in the antagonist binding regionCan only interact with two separate H-bond acceptors in the antagonist binding region 17. Analogues

48 1 © A guanidine unit is highly polar and highly solvatedA guanidine unit is highly polar and highly solvated Solvated water must be removed prior to bindingSolvated water must be removed prior to binding An energy penalty is involvedAn energy penalty is involved The ease of desolvation may affect strength of binding and activityThe ease of desolvation may affect strength of binding and activity A urea group is more hydrophilic than a cyanoguanidine groupA urea group is more hydrophilic than a cyanoguanidine group May explain lower activity of the urea analogueMay explain lower activity of the urea analogue Binding Energy released Desolvation Energy penalty 18. Desolvation Theory 18.1 The process

49 1 © Strategy Increase the hydrophobic character of the planar aminal systemIncrease the hydrophobic character of the planar aminal system Implies less solvationImplies less solvation Implies less of an energy penalty associated with desolvationImplies less of an energy penalty associated with desolvation Implies easier binding and a stronger activityImplies easier binding and a stronger activityResult Antagonist activity of analogues increases as hydrophobic character increasesAntagonist activity of analogues increases as hydrophobic character increases 18. Desolvation Theory 18.2 Hydrophobic analogues

50 1 © Log (activity) = 2.0 log P Desolvation Theory 18.2 Hydrophobic analogues ‘Outrider’

51 1 © Greater activity than expected Hydrophilic group should lower activity Lower activity than expected based on the hydrophobicity of the group present 18. Desolvation Theory 18.2 Hydrophobic analogues

52 1 © 19.1 Proposal Dipole Moment Theory A dipole-dipole interaction takes places between the drug and the binding site on approach of the drugA dipole-dipole interaction takes places between the drug and the binding site on approach of the drug The dipoles line up and orientate the drugThe dipoles line up and orientate the drug Good interaction with the binding site occurs if the binding groups are positioned correctly w.r.t the binding regions - results in good activityGood interaction with the binding site occurs if the binding groups are positioned correctly w.r.t the binding regions - results in good activity Poor interaction occurs if the binding groups are not positioned correctly with respect to the binding regions - leads to poor activityPoor interaction occurs if the binding groups are not positioned correctly with respect to the binding regions - leads to poor activity

53 1 © Approach and orientation Dipole Moments H-Bonding regions Receptor surface Strong hydrogen bonding Receptor surface Weak hydrogen bonding Receptor surface Approach and orientation Receptor surface 19. Dipole Moment Theory 19.2 Dipole-dipole interactions

54 1 © The orientation of the dipole is more important than its strengthThe orientation of the dipole is more important than its strength Log (activity) = 9.12 cos  log P -2.71Log (activity) = 9.12 cos  log P Activity increases as hydrophobicity increases (log P)Activity increases as hydrophobicity increases (log P) The ideal angle of the dipole moment = 30 oThe ideal angle of the dipole moment = 30 o At 30 o,  = 0 o and cos  = 1At 30 o,  = 0 o and cos  = 1 At 30 o, Log (activity) = log P At 30 o, Log (activity) = log P When dipole moment does not equal 30 o, cos  < 1When dipole moment does not equal 30 o, cos  < 1 and activity falls 19. Dipole Moment Theory 19.3 QSAR study including dipole-dipole interactions

55 1 © Contains a nitroketeneaminal groupContains a nitroketeneaminal group Different heterocyclic ringDifferent heterocyclic ring Took over from cimetidine as the most widely sold prescription drug in the worldTook over from cimetidine as the most widely sold prescription drug in the world 20. Ranitidine (Zantac)


Download ppt "1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 22 ANTIULCER AGENTS Part 1: Histamine antagonists."

Similar presentations


Ads by Google