title: Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation.
abstract: Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Nagaswamy
authors.initials: N
authors.lastname: Kumaragurubaran
authors.forename: Lin
authors.initials: L
authors.lastname: Hong
authors.forename: Sarang
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.forename: Heather B
authors.initials: HB
authors.lastname: Miller
authors.forename: Dandepally Srinivasa
authors.initials: DS
authors.lastname: Reddy
authors.forename: Vajira
authors.initials: V
authors.lastname: Weerasena
authors.forename: Robert
authors.initials: R
authors.lastname: Turner
authors.forename: Wanpin
authors.initials: W
authors.lastname: Chang
authors.forename: Gerald
authors.initials: G
authors.lastname: Koelsch
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D013449:Sulfonamides; D001224:Aspartic Acid; C470014:leucyl-alanine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse