title: Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of beta-secretase.
abstract: Fragment-based lead discovery has been successfully applied to the aspartyl protease enzyme beta-secretase (BACE-1). Fragment hits that contained an aminopyridine motif binding to the two catalytic aspartic acid residues in the active site of the enzyme were the chemical starting points. Structure-based design approaches have led to identification of low micromolar lead compounds that retain these interactions and additionally occupy adjacent hydrophobic pockets of the active site. These leads form two subseries, for which compounds 4 (IC50 = 25 microM) and 6c (IC50 = 24 microM) are representative. In the latter series, further optimization has led to 8a (IC50 = 690 nM).
authors.affiliation: Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom. m.congreve@astex-therapeutics.com
authors.forename: Miles
authors.initials: M
authors.lastname: Congreve
authors.forename: David
authors.initials: D
authors.lastname: Aharony
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Albert
authors.forename: Owen
authors.initials: O
authors.lastname: Callaghan
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.forename: Robin A E
authors.initials: RA
authors.lastname: Carr
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.forename: Suzanna
authors.initials: S
authors.lastname: Cowan
authors.forename: Philip D
authors.initials: PD
authors.lastname: Edwards
authors.forename: Martyn
authors.initials: M
authors.lastname: Frederickson
authors.forename: Rachel
authors.initials: R
authors.lastname: McMenamin
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.forename: Sahil
authors.initials: S
authors.lastname: Patel
authors.forename: Nicola
authors.initials: N
authors.lastname: Wallis
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D000634:Aminoquinolines; D007211:Indoles; D008024:Ligands; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human