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

• Published in: Bioorganic chemistry Vol. 95; pp. 103135 - 103149
• Main Authors: Jagtap, Ajit Dhananjay, Kondekar, Nagendra B., Hung, Pei-Yun, Hsieh, Chen-En, Yang, Chia-Ron, Chen, Grace Shiahuy, Chern, Ji-Wang
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.01.2020; Elsevier
• Subjects: 2-amino-3; 4-dihydroquinazolines; Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE-1; Biochemistry & Molecular Biology; Cell Line, Tumor; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Conformation; Non-peptidic aspartyl protease inhibitors; Physical Sciences; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Science & Technology; Structure-Activity Relationship; APP; 2-amino-3; AD; Alzheimer’s disease; cPr; iPr; Bn; Non-peptidic aspartyl protease inhibitors; Aβ; WCA; BACE-1; Structure-activity relationship; Cy; 4-dihydroquinazolines; CFA; POTENT; ALZHEIMERS-DISEASE; APP CLEAVING ENZYME; TARGETS; Alzheimer's disease; STRUCTURE-BASED DESIGN
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103135

[Display omitted] •A novel class of dihydroquinazolines was designed and synthesized to inhibit BACE1.•Key strategy: Relocating the hairpin side-chain α-hydrophobic moiety to position C4 on dihydroquinazolines.•Compound 22a and 22b strongly inhibited BACE1 (CFA, IC50 = 0.38 and 0.49 μM; WCA IC50 = 0.14 and 0.14 μM). 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 S1, S2 and S1′ subsites of BACE-1. Among these derivatives, two compounds exhibited potent BACE-1 inhibitory activity: 4-methyl-substituted (22a, BACE-1 CFA IC50 = 0.38 μM; BACE-1 WCA IC50 = 0.14 μM) and 4-cyclohexylmethyl-substituted (22b, BACE-1 CFA IC50 = 0.49 μM; BACE-1 WCA IC50 = 0.14 μM) 2-amino-3,4-dihydroquinazoline, each bearing a side chain of N-cyclohexyl-N-((1-methyl-1H-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 S2 subsite.