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Macrocycles As Bace 1 Inhibitors

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Macrocycles As Bace 1 Inhibitors

  1. 1. Design and Synthesis of Macrocycles as  -Secretase (BACE-1) Inhibitors for the Treatment of Alzheimer’s Disease
  2. 2. Alzheimer’s Disease Pathophysiology <ul><li>Alzheimer’s Disease is a progressive, devastating and incurable illness </li></ul><ul><li>Some 4.5 million Americans are affected at a cost of $100 billion a year </li></ul>Nitasha Manchanda, Alzheimer’s Disease, Decision Resources , June 2007  /  Secretase
  3. 3. (400,000 compound HTS campaign) Introduction OM 99-2 Heptapeptide K i = 1.6 nM … to small-molecule BACE inhibitors <ul><li>Poor bioavailability </li></ul><ul><li>Metabolically unstable </li></ul>From peptides … Hong, L. et al. Science , 2000, 290, 5489
  4. 4. Macrocylic BACE-1 Inhibitors – Design Target molecule: Synthetic strategy: Bell, Ian M.; et al Journal of Medicinal Chemistry . 2002, 45, 2388-2409
  5. 5. 20 Fold better potency Macrocylic BACE-1 Inhibitors – Initial Synthesis Poor yield-----Difficult for scaling up -----SAR studies Baxter, Ellen E.; Huang, Yifang et al. WO 2007/092839
  6. 6. Two Reactive groups Exploring Alternate Macrocyclization Strategy Reductive amination No literature precedent
  7. 7. Macrocyclization via Reductive Amination NaBH 3 CN/CH 3 OH or NaBH 4 /CH 3 OH not working.
  8. 8. Macrocyclization via Reductive Amination-Continued Imine formation by dehydration
  9. 9. Introducing  -branch to the Macrocycles
  10. 10. Baxter, Ellen E.; Huang, Yifang et al. WO 2007/092839 K i = 5 nM Synthesis of  -Branched Macrocycle
  11. 11. Major Macrocycles Synthesized-SAR Position of Amide : important; Chang of functional groups and ring size: No significant impact ----Great potential for imposing desired pharmaceutical properties.
  12. 12. Macrocycle: In Vivo Testing in Mouse In vivo efficacy (2 mpk, iv, 2 hr) Mouse:  plasma a  - 42%, Rat :  plasma a  -74%, Plasma A  lowing in mice -22% at 25 mpk, PO/dose, 3 h
  13. 13. Acyclic via Macrocyclic compounds K i = 5 nM A  (CHO) cellular IC 50 = 17 nM hERG K i = 1900 nM Plasma A  lowing in mice 22% at 25 mpk, PO/dose 74% at 2 mpk, iv/dose in rat K i = 8 nM A  (CHO) cellular IC 50 = 44 nM hERG K i = 84 nM No in vivo activity <ul><li>Designed and synthesized macrocycles (k i = 5 nM) as BACE-1 enzyme inhibitor </li></ul><ul><li>Starting from HTS hit (k i = 900 nM). </li></ul><ul><li>Developed reductive amination as novel and efficient synthetic approach </li></ul><ul><li>for cyclizing Macrocycles. </li></ul>

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