2-Amino-3, 4-dihydroquinazolines as inhibitors of BACE-1 (β-site APP cleaving enzyme): use of structure based design to convert a micromolar hit into a nanomolar …

…, HL De Winter, CH Reynolds, BA Tounge…

Index: Baxter, Ellen W.; Conway, Kelly A.; Kennis, Ludo; Bischoff, Francois; Mercken, Marc H.; De Winter, Hans L.; 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. Journal of Medicinal Chemistry, 2007 , vol. 50, # 18 p. 4261 - 4264

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Citation Number: 119

Abstract

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 (Asp32, Asp228). BACE-1 inhibitory potency was increased (0.9 μM to 11 nM K i) by substitution into the unoccupied S1'pocket.