title: Synthesis and evaluation of novel prodrugs of caspase inhibitors.
abstract: A novel type of caspase inhibitor prodrug that improves systemic exposure after oral administration in rats has been designed. Such a prodrug, based on a 6,6a-dihydrofuro[3,2-d]oxazol-5(3aH)-one motif, has the advantage of rapidly liberating the active inhibitor without producing any cleavage by-product. Prodrugs 6-8, are synthesised in a high yielding one-step transformation from the active parents with high diastereomeric excess.
authors: Chemistry Department, Vertex Pharmaceuticals, 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK. jean-damien_charrier@vrtx.com
authors: Jean-Damien
authors: JD
authors: Charrier
authors: Steven J
authors: SJ
authors: Durrant
authors: John
authors: J
authors: Studley
authors: Linda
authors: L
authors: Lawes
authors: Peter
authors: P
authors: Weber
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis; D019540:Area Under Curve; D061945:Caspase Inhibitors; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D008956:Models, Chemical; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D057786:Peptidomimetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010455:Peptides; D057786:Peptidomimetics; D011355:Prodrugs