the discovery of Raltegravir

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the discovery of Raltegravir

  1. 1. The Discovery of Raltegravir (MK-The Discovery of Raltegravir (MK- 518), an Integrase Inhibitor for the518), an Integrase Inhibitor for the Treatment of HIV InfectionTreatment of HIV Infection By Dr. Michael Rowley IRBM, via Pontina Km 30,600, Pomezia, Rome 00040, Italy Summarized by Qinglin Che for Synta Chemistry Enhancement Program
  2. 2. Some Facts about HIV/AIDS 2.7 million in 2007 2.0 million in 2007 Total in 2007 33 million
  3. 3. Schematic Illustration of HIV-1 Virion Illustration of HIV-1 Virion Lipid bilayerLipid bilayer Viral envelopeViral envelope 72 spikes72 spikes Structure of Hiv particle Viral envelopeViral envelope
  4. 4. Image of HIV Infected T-Cells Size of HIV Particle: ~100-150 nmSize of HIV Particle: ~100-150 nm HIV-1 particles assembling at the surface of anHIV-1 particles assembling at the surface of an infected macrophageinfected macrophage
  5. 5. HIV Viral Life Cycle CXCR4CXCR4 CCR5CCR5 Intigrase inhibitorIntigrase inhibitor 0 until 20080 until 2008 Reverse Transcriiptase InhibitorReverse Transcriiptase Inhibitor 11 (NRTI) + 4 (NtRTI)11 (NRTI) + 4 (NtRTI) Protease inhibitorProtease inhibitor 99
  6. 6. The Chemistry of Integrase
  7. 7. HCV NS5B inhibitors Finding the lead: From HCV NS5B to HIV Integrase inhibitors HIV integrase & HCV NS5B -share mechanistic similarities - Need two divalent metal ions for their phosphoryltransferas e activities.
  8. 8. Compound 3: Dihydroxy pyrimidine acid Low permibility, Too polar Compound 4: HCV NS5B inactive HIV integrase IC50 85 nM Finding the lead: From HCV NS5B to HIV Integrase inhibitors HCV NS5B inhibitors
  9. 9. Discovery of L-870812 and L-870810Discovery of L-870812 and L-870810 Compound 5:Compound 5: •formform West PointWest Point •Improved PKImproved PK •Low potencyLow potency Compound 4:Compound 4: •FromFrom IRBMIRBM •high potencyhigh potency From compound 4 & 5, after optimization, L-870810 was discovered at West Point Con of (4): a. low activity in the cell-based assay > 5 µM b. low bioavailability (~15%) c. High plasma protein binding Compound L-870810 (MK-624):Compound L-870810 (MK-624): •formform West PointWest Point •Discontinued after Phase II due toDiscontinued after Phase II due to toxicity in dogs during long termtoxicity in dogs during long term dosingdosing
  10. 10. Lead Optimization: Investigation of Benzyl AmideLead Optimization: Investigation of Benzyl Amide 1. NH is needed 2. 1-2 methylene linker is required 3. Heterocyle ok, Potency correlated with Log P. 1. Branching linker is no good. 1. NH is needed 2. 1-2 methylene linker is required 3. Heterocyle ok, Potency correlated with Log P. 1. Branching linker is no good.
  11. 11. Lead Optimization: Investigation on Benzyl SubstitutionLead Optimization: Investigation on Benzyl Substitution Conclusion: 1. Para > meta > ortho 2. 4-F > 4-Cl > 4-Br > 4-CF3 > others Conclusion: 1. Para > meta > ortho 2. 4-F > 4-Cl > 4-Br > 4-CF3 > others
  12. 12. After Extensive Investigation…..After Extensive Investigation….. cell penetration, protein binding, PK and other parameterscell penetration, protein binding, PK and other parameters
  13. 13. Lead Optimization: 2-Substitution Remining Issue:. Still very low activity in cell-based assay! Even in low serum level assay (10% FBS). Compound 35, Spread CIC95 >5μM PhCH2
  14. 14. Compound 36: Adding a basic group confers cell activity New Lead Compound 36: -very good PK, high bioavailability: rat F 59%, dog F 93% -low clearance: rat 14 ml/min/kg, dog 0.5 ml/min/kg -protein binding (>99%) -Shift in a cell-based assay between low and high serum Conditions is high!. activity in 50% NHS (> 10μM)
  15. 15. for CRAC chemists: THE IMPORTANCE OF PROTEIN BINDING Lipophilic acid compound Lipophilicity (logD) ↑ albumin binding ↑
  16. 16. Shift in cell-based assays and Protein Binding Low protein binding low shift! But when <90%, shift < 4, good enough Optimum protein binding range 80%~90% Low protein binding High Clearance Need >80%
  17. 17. Direction 1 from compound 36: Simple Acyclic 2-Substituents 37: enzyme activity ok, But lower in FBS, due to low cell penetration 38: 1 methyl group FBS 10 times increase , and good NHS activity 39: 2 methyl groups, no chiral center, highly active both low and high serum 40, 41 ethyl or NH both detrimental 37: enzyme activity ok, But lower in FBS, due to low cell penetration 38: 1 methyl group FBS 10 times increase , and good NHS activity 39: 2 methyl groups, no chiral center, highly active both low and high serum 40, 41 ethyl or NH both detrimental
  18. 18. Compound 39, the First Candidate with development potential! Not CYP450 inhibitor, not CYP3A4 inducer, no oxidative metabolism Major Metabolite: 5-O-glucuronide
  19. 19. Direction 2 from compound 36: Simple Cyclic 2-Substituents A basic nitrogen was tolerated! 2-NH > 3-NH > 4-NH -NMe > -NH A basic nitrogen was tolerated! 2-NH > 3-NH > 4-NH -NMe > -NH
  20. 20. An important discovery: N-methylpyrimidines A side reaction?A side reaction?
  21. 21. An important discovery: N-methylpyrimidines
  22. 22. “it had two important improvements: The first was that the protein binding was considerably lower (a factor that we had struggled with in the dihydroxypyrimidine series) and, the second was that rat PK was improved, with better oral bioavailability and lower plasma clearance. We reasoned that it would be easier to improve potency in a series with good protein binding and PK than the converse and turned our attention to the N-Me pyrimidinone series.” “it had two important improvements: The first was that the protein binding was considerably lower (a factor that we had struggled with in the dihydroxypyrimidine series) and, the second was that rat PK was improved, with better oral bioavailability and lower plasma clearance. We reasoned that it would be easier to improve potency in a series with good protein binding and PK than the converse and turned our attention to the N-Me pyrimidinone series.”
  23. 23. N-METHYLPYRIMIDINES WITH CYCLIC 2-SUBSTITUENTS
  24. 24. N-METHYLPYRIMIDINES WITH CYCLIC 2-SUBSTITUENTS
  25. 25. N-METHYLPYRIMIDINES WITH CYCLIC 2-SUBSTITUENTS
  26. 26. Back to ACYCLIC BASIC SUBSTITUENTS on N-METHYLPYRIMIDINES
  27. 27. N-METHYLPYRIMIDINES WITH NON-BASIC POLOR SUBSTITUENTS
  28. 28. N-Me-PYRIMIDINES WITH NON-BASIC SUBSTITUENTS (cont.)
  29. 29. Evolution from Hit to Lead to preclinical candidate 66
  30. 30. RESISTANCE PROFILING
  31. 31. Fight is not over DISCOVERY OF RALTEGRAVIR
  32. 32. DISCOVERY OF RALTEGRAVIR (cont.) Low permeability High Protein binding
  33. 33. RALTEGRAVIR , First-In-Class •QC IC50 10 nM •Spread CIC95 19 nM (10% FBS) •Spread CIC95 31 nM (50% NHS) •Protein Binding •PK F% 45% in rat, 69% in dog •Plasma clearance 1.8 rat, 11 dog •No CYP450 inhibitor •No CYP3A4 inducer •No UGT1A1 inhibitor •Resistance Profiling: excellent •Safety in human •Efficacy short term as monotherapy •long term in combination
  34. 34. The Synthesis of MK-518
  35. 35. S-1360 from GSKS-1360 from GSK -Licenced from Shionogi-Licenced from Shionogi -Diketoacid derivative-Diketoacid derivative -Low efficacy, extramely poor bioavailability-Low efficacy, extramely poor bioavailability -discontinued in Phase II-discontinued in Phase II GS-9137 (elvitegravir) from Gilead Licenced from Japan Tobacco Metabolised in part by Cyp3A4 co-doing with ritonayir (a HIV protease inhibitor also inhibit Cyp3A4) Phase III clinical trial Ongoing nowBMS compounds similar to RaltegravirBMS compounds similar to Raltegravir Discontinued in Phase IIb due To hepatotoxicities Other HIV Integrase Inhibitors
  36. 36. First-in-ClassFirst-in-Class What do you think?What do you think? First-in-ClassFirst-in-Class What do you think?What do you think? • Trial and error, learning curve, solid science,Trial and error, learning curve, solid science, be prepared of failure in the beginningbe prepared of failure in the beginning • Competition. Not guaranteed winner among otherCompetition. Not guaranteed winner among other big pharmasbig pharmas • Some luck is needed!Some luck is needed!
  37. 37. A Quote from Barbara Ehrenreich “From the point of view of the pharmaceutical industry, the AIDS problem has already been solved. After all, we already have a drug which can be sold at the incredible price of $8, 000 an annual dose, and which has the added virtue of not diminishing the market by actually curing anyone.” Ehrenreich, Barbara (from wikipedia) In clinical trials patients taking Raltegravir achieved viral loads less than 50 copies per millitre sooner than those taking similarly potent Non-nucleoside Reverse Transcriptase Inhibitors or Protease Inhibitors. This statistically significant difference in viral load reduction has caused some HIV researchers to begin questioning long held paradigms about HIV viral dynamics and decay. Research into Raltegravir's ability to affect latent viral reservoirs and possibly aid in the eradication of HIV is currently ongoing. Ongoing Clinical Trials: Depletion of Latent HIV in CD4 Cells
  38. 38. How difficult to get a first-in-class drug to the market from scratch
  39. 39. Raltegravir Potassium Salt: at a glance

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