Synthesis and SAR of 2-carboxylic acid indoles as inhibitors of plasminogen activator inhibitor-1.
We synthesized and evaluated a novel series of 2-carboxylic acid indole-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). Systematic modification of the N-1 position and the 5-position of the indole scaffold resulted in the identification of several compounds that showed good potency against PAI-1 in the spectrophotometric assay. This potency did not always translate to the antibody assay. Solubility and serum protein binding studies on selected analogs revealed that protein binding might be a factor in the poor correlation between the two assays.
Chemical and Screening Sciences, Wyeth Research, Collegeville, PA 19426, USA. hub@wyeth.com
Baihua
B
Hu
James W
JW
Jetter
Jay E
JE
Wrobel
Thomas M
TM
Antrilli
Jean S
JS
Bauer
Li
L
Di
Sergiusz
S
Polakowski
Uday
U
Jain
David L
DL
Crandall
D001665:Binding Sites; D002264:Carboxylic Acids; D004797:Enzyme-Linked Immunosorbent Assay; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D013053:Spectrophotometry; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; C058980:indole-2-carboxylic acid