title: Thiophene substituted acylguanidines as BACE1 inhibitors.
abstract: A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE1 and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, CN8000, Princeton, NJ 08543-8000, USA. fobarew@wyeth.com
authors.forename: William F
authors.initials: WF
authors.lastname: Fobare
authors.forename: William R
authors.initials: WR
authors.lastname: Solvibile
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Eric
authors.initials: E
authors.lastname: Manas
authors.forename: Jim
authors.initials: J
authors.lastname: Turner
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Erik
authors.initials: E
authors.lastname: Wagner
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cowling
authors.forename: Guixan
authors.initials: G
authors.lastname: Jin
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006146:Guanidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008958:Models, Molecular; D011758:Pyrroles / Q000737:chemistry; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D007202:Indicators and Reagents; D011758:Pyrroles; D013876:Thiophenes; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human