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DESIGN OF A NOVEL ANXIOLYTIC AND ANTIDEPRESSANT AGENT
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Target - Serotonin Receptor
Notes Important receptor in central nervous system 7 types (5-HT1 - 5HT7) and 14 subtypes G-Protein-coupled receptors (except 5-HT3) Three subtypes of 5-HT2 receptor (5-HT2A 5-HT2B 5-HT2C) 5-HT2C receptor thought to be involved in anxiety mCPP is an agonist with some selectivity for 5-HT2C receptor mCPP causes anxiety in human and animal studies Antagonist with selectivity for 5-HT2C receptor may be useful in treating anxiety meta-Chlorophenylpiperazine (mCPP)
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(5-Hydroxytryptamine)
Natural Ligand Serotonin (5-Hydroxytryptamine) Notes Serotonin is a neurotransmitter Abnormal levels of serotonin are related to various disorders (e.g. anxiety, depression, migraine) Indole ring system is present
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Aims of Drug Design 5-HT2A and 5-HT2C receptors predominate in CNS
Selectivity for 5-HT2C receptor Selectivity over 5-HT2A is more important than over 5-HT2B 5-HT2B predominates in peripheral nervous system 5-HT2A and 5-HT2C receptors predominate in CNS Resistance to drug metabolism No effect on metabolic enzymes (drug-drug interactions) Aqueous solubility Non-sedating No interaction with alcohol Fast onset of action High response rate No withdrawal effects
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Testing Procedures In vitro tests
Radioligand binding studies on 5-HT2A, 5-HT2B and 5-HT2C receptor subtypes Tests for activity against cytochrome P450 enzymes In vivo tests Ability to block hypoactivity in rats caused by mCPP Modelling studies Drug design carried out on model binding sites
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Lead Compound Produced by Lilly Pharmaceuticals Serotonin antagonist
Urea Indole Aromatic Produced by Lilly Pharmaceuticals Serotonin antagonist Insoluble in water
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From Lead Compound to SB 200646
Pyridine SB Notes Substituents removed from indole ring (simplification) Pyridine ring introduced (ring variation) Pyridine ring more polar - increases water solubility Urea link at optimum positions for both ring systems First selective 5-HT2B/2C antagonist 50-fold selectivity over 5-HT2A receptor Modest in vitro activity Some oral activity in vivo
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From SB to SB SB Rigidification SB Tricyclic ring system Extra ring Metabolically labile Notes Rigidification limits number of possible conformations Rigidify structure such that active conformation still allowed Increased chance of active conformation being present 10-fold increase of in vitro affinity 160-fold selectivity over 5-HT2A receptor 4-fold increase of in vivo activity
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From SB 200646 to SB 206553 Conformation of SB 206553
Overall structure is roughly planar
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7. From SB 200646 to SB 206553 Metabolism of SB 206553
Metabolically labile N-Demethylation Metabolite is active but non-selective
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Analogues of SB Substitution bad Variation permitted Notes Methyl group replacable with Et, Pr or iPr Slightly increased selectivity for 5-HT2C over 5-HT2A Hydrophobic pocket available for N-alkyl group Slightly bigger for 5-HT2C receptor
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Analogues of SB 206553 Ring variation strategy No methyl group
Pyrrole Ring variation strategy Thipohene No methyl group Loss of selectivity No methyl group Furan Retains Me group More stable to metabolism Good in vitro affinity and selectivity Poor oral activity Poorly absorbed from gut or rapidly metabolized Administered by IV injection
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3D QSAR studies of SB 206553 and analogues
Notes Structures overlaid using urea group Dark and light blue = areas accessed by compounds having 5-HT2C activity Light blue = disallowed area for 5-HT2A activity Light blue area = region of N-methyl group of SB
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Molecular modelling studies of SB 206553 and analogues
Notes Model receptor binding site created SB docked into binding site Carbonyl oxygen of urea group is crucial for activity Positioned to form hydrogen bond to Ser-312 - Ser-312 present in 5-HT2 receptors but not 5-HT1 receptors - binding to Ser-312 thought to be important for selectivity for 5-HT2 receptors over 5-HT1 receptors Carbonyl oxygen interacts with Ser-312 and Ser-315 Aromatic rings positioned into hydrophobic pockets
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Molecular modelling studies of SB 206553 and analogues
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Molecular modelling studies of SB 206553 and analogues
1 3 8 4 Phe-223 Trp-324 Phe-327 Phe-328 Phe-220 Phe-224 Val-212 V al-608 Hydrophobic pocket
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Molecular modelling studies of SB 206553 and analogues
Notes Val-608 and Val-212 are present in the hydrophobic pocket occupied by the N-methyl group Bulkier leucine groups are present in the model binding site for the 5-HT2A receptor Hydrophobic pocket is smaller for the 5-HT2A receptor More difficult for N-methyl group of SB to fit the 5-HT2A receptor May account for selectivity of SB
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From SB to SB Aim To replace the metabolically labile N-methyl group with a metabolically stable group The new group must bind to the hydrophobic pocket for selectivity SB Indolines Notes Indole ring is removed - simplification Indoline structures are synthesized with varying substituents Substituent X needs to bind to the hydrophobic pocket Electron-withdrawing substituent at position 6 is preferred Thioether or ether at position 5 is beneficial
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From SB to SB SB221284 Electron-withdrawing Fits hydrophobic pocket Metabolically stable SB221284 Fits hydrophobic pocket Metabolically stable SB221284 Inhibits cytochrome P450 enzymes Notes Best balance of affinity vs selectivity Potent inhibitor of 5-HT2B and 5-HT2C receptors Good selectivity over 5-HT2A receptor Inhibits cytochrome P450 enzymes Pyridine N is responsible for inhibiting cyt P450 enzymes Selectivity increases for SEt, SnPr or OiPr, but affinity falls
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Modelling Studies on SB 221284
Notes SB is docked into the model binding site for the 5-HT2C receptor Pyridine and indoline rings are positioned in hydrophobic pockets Hydrogen bonding interactions take place with serine residues S-Methyl group fits the hydrophobic pocket CF3 group orientates the thiomethyl group into the correct conformation CF3 acts as a conformational blocker
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Modelling Studies on SB 221284
r- 1 3 8 4 Phe-223 Trp-324 Phe-327 Phe-328 Phe-220 Phe-224 Val-212 V al-608 Hydrophobic pocket Note Vacant areas are available in the hydrophobic pocket accommodating the pyridine ring
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3D-QSAR Studies on SB 221284 55 Analogues are synthesized
Notes 55 Analogues are synthesized Analogues are docked into the model receptor Receptor-ligand complex is minimized Ligands are removed and subjected to CoMFA analysis Predicted affinity versus actual affinity demonstrates a good relationship
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3D-QSAR Studies on SB Notes Steric fields are more important than electrostatic fields Dark blue represents beneficial areas Light blue represents detrimental areas Large number of detrimental areas round the indoline ring Suggests a tight binding pocket Little scope for modification
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From SB to SB Inhibits cytochrome P450 enzymes Notes Aromatic ring is best placed at position 5 Increased binding interactions with hydrophobic pocket Slightly increased affinity and selectivity Aromatic ring acts as a steric shield for pyridine 100-fold decrease in cytochrome P450 inhibition Level of cytP450 enzyme inhibition is still unacceptable Low oral activity Electron-rich aromatic ring is possibly susceptible to metabolism
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From SB 221284 to SB 228357 Structure II
Vary ring and rigidification Structure II Pyridine ring is more polar leading to increased water solubility 10-fold increase in affinity due to additional binding interactions Lower selectivity between 5-HT2C and 5-HT2A receptors Structure III Selectivity is recovered by adding a methyl substituent Slightly increased affinity for the 5-HT2C receptor Moderate oral activity Slight drop in cytochrome P450 inhibition
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From SB to SB Steric clash Structure III Notes Methyl group acts as a conformational blocker Forces rings to be orthogonal Orthogonal rings favored by 5-HT2C receptor but not 5-HT2A receptor
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From SB to SB Ring variation 4’ 5 Structure III Notes Pyridine nitrogen is responsible for inhibiting cytochrome P450 enzymes Pyridine is replaced by an aromatic ring (ring variation) Poor water solubility Water solubility is improved by a pyridine substituent (R) Substituent is best at position 3 (variation of substituents)
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From SB to SB 4’ 5 Ring variation Structure III Notes Pyridine nitrogen is responsible for inhibiting cytochrome P450 enzymes Pyridine is replaced by an aromatic ring (ring variation) Poor water solubility Water solubility is improved by a pyridine substituent (R) Substituent is best at position 3 (variation of substituents)
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From SB 221284 to SB 228357 Improved selectivity
4’ 5 Ring variation Structure III Improved selectivity Higher 5-HT2C affinity Potent oral activity Still inhibits cytochrome P450 enzymes
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From SB to SB 3 Vary substituents Structure VI Electron rich Notes Methyl substituent moved to the ortho position Acts as a conformational blocker Aromatic and pyridine rings cannot be co-planar Increased selectivity for the 5-HT2C over the 5-HT2A receptor Short duration of action Electron-rich aromatic ring is susceptible to metabolism
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From SB to SB Bad Electron rich Structure VI Structure VIII Notes Analogues made with electron-withdrawing substituents on the aromatic ring Substitution at 2 and 6 is bad - ring is twisted out of plane with the urea group Substitution at positions 4 and 5 is acceptable
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From SB 221284 to SB 228357 Increased duration of action (6 hours)
Electron rich Structure VI SB Increased duration of action (6 hours) Modeling studies suggest extra space available in hydrophobic pocket Further extension possible
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From SB to SB SB Structure IX Linker Notes Substitution pattern is altered to para Linker oxygen atom is inserted Pushes pyridine further into the hydrophobic pocket Poor oral activity due possibly to reduced solubility
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15. From SB to SB Linker SB Structure IX Structure X Original pyridine restored to increase water solubility
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From SB 228357 to SB 243213 Linker SB 228357 Structure IX Structure X
Structure XI
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From SB to SB Structure XI Notes ortho Methyl group acts as a conformational blocker Increases torsion angle between the pyridine rings Increased selectivity and affinity for 5-HT2C receptor 80-fold selectivity over 5-HT2B receptor Low cyctochrome P450 activity Good in vivo activity
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From SB to SB Structure XI SB Notes Methoxy group is replaced with a methyl group Less liable to metabolism Good profile of affinity, activity and selectivity Negligible cytochrome P450 activity Better aqueous solubility than SB Entered phase I clinical trials as a non-sedating antidepressant / anxiolytic
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From SB to SB Modelling studies for SB Pyridine ring substituent well inserted into hydrophobic pocket
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From SB 228357 to SB 243213 Binding interactions for SB 243213 S e r-
Phe-223 Trp-324 Phe-327 Phe-328 Phe-220 Phe-224 Val-212 V al-608
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