Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of beta-secretase.
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).
Congreve
Miles
M
Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom. m.congreve@astex-therapeutics.com
Aharony
David
D
Albert
Jeffrey
J
Callaghan
Owen
O
Campbell
James
J
Carr
Robin A E
RA
Chessari
Gianni
G
Cowan
Suzanna
S
Edwards
Philip D
PD
Frederickson
Martyn
M
McMenamin
Rachel
R
Murray
Christopher W
CW
Patel
Sahil
S
Wallis
Nicola
N
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
D000634:Aminoquinolines; D007211:Indoles; D008024:Ligands; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human