title: Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands.
abstract: Structure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P2-ligand and a substituted pyrazole as the P3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S2-S3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (Ki=1.1 nM) and very good cellular inhibitory activity (IC50=39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of Abeta40 production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors.
authors: Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
authors: Arun K
authors: AK
authors: Ghosh
authors: Nagaswamy
authors: N
authors: Kumaragurubaran
authors: Lin
authors: L
authors: Hong
authors: Sarang S
authors: SS
authors: Kulkarni
authors: Xiaoming
authors: X
authors: Xu
authors: Wanpin
authors: W
authors: Chang
authors: Vajira
authors: V
authors: Weerasena
authors: Robert
authors: R
authors: Turner
authors: Gerald
authors: G
authors: Koelsch
authors: Geoffrey
authors: G
authors: Bilcer
authors: Jordan
authors: J
authors: Tang
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry; D015195:Drug Design; D005260:Female; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D004151:Dipeptides; C520858:GRL 7234; D008024:Ligands; D010446:Peptide Fragments; D010795:Phthalic Acids; D013449:Sulfonamides; C078592:amyloid beta-protein (1-40); C470014:leucyl-alanine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D014633:Valine