4-Substituted 2-amino-3,4-dihydroquinazolines with a 3-hairpin turn side chain as novel inhibitors of BACE-1

Abstract Herein, we report the identification, design, and synthesis of a series of 4-substituted 2-amino-3,4-dihydroquinazolines with hairpin turn side chains as novel inhibitors of BACE-1. The dihydroquinazoline derivatives were rationally designed by modifying the amide group and relocating the α -hydrophobic substituent on the hairpin turn side chain of lead compound 2 to the C4-position on the 3,4-dihydroquinazoline scaffold to facilitate interactions with the S 1 , S 2 and S 1 ′ subsites of BACE-1. Among these derivatives, two compounds exhibited potent BACE-1 inhibitory activity: 4-methyl-substituted ( 22a , BACE-1 CFA IC 50 = 0.38 μM; BACE-1 WCA IC 50 = 0.14 μM) and 4-cyclohexylmethyl-substituted ( 22b , BACE-1 CFA IC 50 = 0.49 μM; BACE-1 WCA IC 50 = 0.14 μM) 2-amino-3,4-dihydroquinazoline, each bearing a side chain of N -cyclohexyl- N -((1-methyl-1 H -pyrazol-4-yl)methyl amide. The results suggest that the structural modifications maintain the hairpin turn topology similar to that of compound 2 and provide an additional interaction with the S 2 subsite.