Thiophene substituted acylguanidines as BACE1 inhibitors.
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.
Fobare
William F
WF
Chemical and Screening Sciences, Wyeth Research, CN8000, Princeton, NJ 08543-8000, USA. fobarew@wyeth.com
Solvibile
William R
WR
Robichaud
Albert J
AJ
Malamas
Michael S
MS
Manas
Eric
E
Turner
Jim
J
Hu
Yun
Y
Wagner
Erik
E
Chopra
Rajiv
R
Cowling
Rebecca
R
Jin
Guixan
G
Bard
Jonathan
J
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*
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