title: Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors.
abstract: Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13 nM) and cellular (IC(50)=21 nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Satyendra
authors.initials: S
authors.lastname: Pandey
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Gangarajula
authors.forename: Sarang
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.forename: Kalapala Venkateswara
authors.initials: KV
authors.lastname: Rao
authors.forename: Xiangping
authors.initials: X
authors.lastname: Huang
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D013844:Thiazoles; C031280:pyrazole; D053829:Amyloid Precursor Protein Secretases