1 / 39

DESIGN OF A NOVEL ANXIOLYTIC AND ANTIDEPRESSANT AGENT

DESIGN OF A NOVEL ANXIOLYTIC AND ANTIDEPRESSANT AGENT. meta -Chlorophenylpiperazine (mCPP). Target - Serotonin Receptor. Notes Important receptor in central nervous system 7 types (5-HT 1 - 5HT 7 ) and 14 subtypes G-Protein-coupled receptors (except 5-HT 3 )

alaire
Télécharger la présentation

DESIGN OF A NOVEL ANXIOLYTIC AND ANTIDEPRESSANT AGENT

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. DESIGN OF A NOVEL ANXIOLYTIC AND ANTIDEPRESSANT AGENT

  2. meta-Chlorophenylpiperazine (mCPP) 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

  3. 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

  4. Aims of Drug Design • 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

  5. 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

  6. Urea Aromatic Indole • Produced by Lilly Pharmaceuticals • Serotonin antagonist • Insoluble in water Lead Compound

  7. Pyridine SB 200646 SB 200646 From Lead Compound to SB 200646 • 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

  8. Rigidification Extra ring Metabolically labile SB 200646 SB 206553 From SB 200646 to SB 206553 Tricyclic ring system • 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

  9. From SB 200646 to SB 206553 Conformation of SB 206553 Overall structure is roughly planar

  10. Metabolism of SB 206553 N-Demethylation Metabolically labile Metabolite is active but non-selective 7. From SB 200646 to SB 206553

  11. Analogues of SB 206553 Substitution bad 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

  12. Pyrrole Furan Thipohene • No methyl group • Loss of selectivity No methyl group • 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 Analogues of SB 206553 Ring variation strategy

  13. 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 206553

  14. Molecular modelling studies of SB 206553 and analogues • Notes • Model receptor binding site created • SB 206553 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

  15. Molecular modelling studies of SB 206553 and analogues

  16. S e r- 1 4 1 S e r- 1 3 8 Phe-328 Phe-327 Trp-324 V al-608 Hydrophobic pocket Phe-220 Phe-223 Val-212 Hydrophobic pocket Phe-224 Molecular modelling studies of SB 206553 and analogues

  17. 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 206553 to fit the 5-HT2A receptor • May account for selectivity of SB 206553

  18. Indolines SB 206553 From SB 206553 to SB 221284 • 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 • 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

  19. Electron-withdrawing Fits hydrophobic pocket Metabolically stable Fits hydrophobic pocket Metabolically stable Inhibits cytochrome P450 enzymes SB221284 SB221284 SB221284 From SB 206553 to SB 221284 • 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

  20. Modelling Studies on SB 221284 • Notes • SB 221284 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

  21. S e r- 1 4 1 S e r- 1 3 8 Phe-328 Phe-327 Trp-324 V al-608 Hydrophobic pocket Phe-220 Phe-223 Val-212 Hydrophobic pocket Phe-224 Modelling Studies on SB 221284 Note Vacant areas are available in the hydrophobic pocket accommodating the pyridine ring

  22. 3D-QSAR Studies on SB 221284 • 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

  23. 3D-QSAR Studies on SB 221284 • 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

  24. Inhibits cytochrome P450 enzymes From SB 221284 to SB 228357 • 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

  25. Vary ring and rigidification From SB 221284 to SB 228357 • 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

  26. Steric clash From SB 221284 to SB 228357 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

  27. 4’ Ring variation 5 From SB 221284 to SB 228357 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)

  28. 4’ 5 From SB 221284 to SB 228357 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)

  29. 4’ 5 • Improved selectivity • Higher 5-HT2C affinity • Potent oral activity • Still inhibits cytochrome P450 enzymes From SB 221284 to SB 228357 Ring variation Structure III

  30. Vary substituents 3 Structure VI From SB 221284 to SB 228357 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

  31. Bad Electron rich Bad Structure VIII Structure VI From SB 221284 to SB 228357 • 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

  32. Electron rich SB 228357 Structure VI • Increased duration of action (6 hours) • Modeling studies suggest extra space available in hydrophobic pocket • Further extension possible From SB 221284 to SB 228357

  33. Linker Structure IX SB 228357 From SB 228357 to SB 243213 • 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

  34. Structure X Linker Original pyridine restored to increase water solubility 15. From SB 228357 to SB 243213 Structure IX SB 228357

  35. Structure X Structure XI Linker From SB 228357 to SB 243213 Structure IX SB 228357

  36. Structure XI From SB 228357 to SB 243213 • 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

  37. Structure XI SB 243213 From SB 228357 to SB 243213 • 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 228357 • Entered phase I clinical trials as a non-sedating antidepressant / anxiolytic

  38. From SB 228357 to SB 243213 Modelling studies for SB 243213 Pyridine ring substituent well inserted into hydrophobic pocket

  39. S e r- 1 4 1 S e r- 1 3 8 Phe-328 Phe-327 V al-608 Trp-324 Phe-220 Phe-223 Val-212 Phe-224 From SB 228357 to SB 243213 Binding interactions for SB 243213

More Related