N-(3-(2-amino-6,6-difluoro-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-4-yl)-phenyl)-amides as BACE1 inhibitors: a patent evaluation of WO2013041499.
A new series of oxazin amides have been synthesized from isoxazoles using a reaction to increase the heterocyclic ring size and were evaluated as BACE1 inhibitors. The innovative compounds were able to diminish amyloid-β peptide concentration in cell and proved to be selective toward peptidases from the same family. Further studies on the toxicity of this series showed that these new molecules were not recognized by P-glycoprotein and that they were unsusceptible to rapid metabolization by cytochrome P450 or glutathione conjugation. These results indicate that such compounds could be useful in developing drugs to fight Alzheimer's disease and that this novel oxazin scaffold should be considered as a starting point to tackle this pathology.
Institut Européen de Chimie et Biologie (IECB), CNRS UMR 5248 Chimie et Biologie des Membranes et des Nano-objets (CBMN) CBMN-IECB , 2 rue Robert Escarpit, 33607 Pessac Cedex , France j.dessolin@iecb.u-bordeaux.fr.
Jean
J
Dessolin
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000523:psychology; D000577:Amides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004335:Drug and Narcotic Control; D006801:Humans; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010330:Patents as Topic; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000577:Amides; D016564:Amyloid beta-Protein Precursor; D010078:Oxazines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human