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Retrometabolic  Drug Design ,[object Object],[object Object],[object Object],[object Object],[object Object],(Retrometabolism-based drug design and targeting  Burger’s medicinal chemistry and drug discovery  Vol.2 chapter 15 2003)
Prof. Nicholas Bodor ,[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],TEOREMA di ARIENS “ LESS CHEMICAL, LESS TOXICITY” MIGLIORE INDICE TERAPEUTICO
Chemical Delivery System (CDS) / Soft drug (SD)
Chemical Delivery System Tipi di approcci ,[object Object],[object Object],[object Object]
1,4-diidrotrigonellina/trigonellina ,[object Object],[object Object],[object Object],[object Object]
Brain-targeting CSD  (trigonellina)
Complessi ciclodestrina ,[object Object],[object Object],[object Object],[object Object],[object Object]
Brain-targeting CSD  (trigonellina)
Fattore di arricchimento nel cervello
Brain-targeting CSD  (molecular packaging)
[object Object],[object Object],[object Object],Brain-targeting CSD   (molecular packaging)
1° step: diffusione passiva 2° step: ossidazione 3° step: idrolisi gruppo L  esterasi/lipasi 4° step: idrolisi gruppo T+S  dipeptidil peptidasi
Brain-targeting CSD  (fosfonati)
CSD enzima-attivato sito-specifico
CSD con ancoraggio transiente al recettore
Brevetti ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Soft Drug Tipi di approcci ,[object Object],[object Object],[object Object],[object Object],[object Object]
Analogue soft drug ,[object Object],[object Object],[object Object],[object Object],[object Object]
Carbossilesterasi ,[object Object],[object Object],[object Object],[object Object],[object Object]
Antibatterici ?
Antipsoriasi
ACE  inibitori
Anticolinergici
Inactive metabolite-based soft drug ,[object Object],[object Object],[object Object],[object Object],[object Object]
Anticolinergici
Attività
SAR di anticolinergici
Analgesici oppioidi
 -bloccanti
Active metabolite-based soft drug
Activated soft drug ,[object Object],[object Object],[object Object]
Pro-soft drug
Antiinfiammatori
Vantaggi ,[object Object],[object Object],[object Object],[object Object]
Computer-Assisted Design ,[object Object],[object Object],[object Object],[object Object],[object Object]
Scelta dei derivati isosterici/isoelettronici RF=11.16 RF=12.09 RF=15.76 RF=1.85
Labilità idrolitica ,[object Object],[object Object]
Brevetti ,[object Object],[object Object],[object Object]
(segue) ,[object Object],[object Object],[object Object]
IVAX corporation ,[object Object],[object Object],[object Object],[object Object]
ARYx Therapeutics, Inc.
(segue)  Prodotti in fase di ricerca
Marketed drugs ,[object Object],[object Object],[object Object]

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Retrometabolic drug design

Editor's Notes

  1. Indicazione effetti cognitivi, sintomi menopausa, ischemia occlusione ateria, protezione neuroni colinergici 2-idrossipropil beta ciclodestrina solubilità aumentata di 250.000 volte (65 ng/ml a 16.4 mg/ml)
  2. Aumentare il