Article
2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead.
Journal of medicinal chemistry - 6 Sept 2007
Baxter Ellen W, Conway Kelly A, Kennis Ludo, Bischoff François, Mercken Marc H, Winter Hans L De, Reynolds Charles H, Tounge Brett A, Luo Chi, Scott Malcolm K, Huang Yifang, Braeken Mirielle, Pieters Serge M A, Berthelot Didier J C, Masure Stefan, Bruinzeel Wouter D, Jordan Alfonzo D, Parker Michael H, Boyd Robert E, Qu Junya, Alexander Richard S, Brenneman Douglas E, Reitz Allen B
Abstract excerpt
A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by...
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