Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 2: optimization of BX-517.
Based on the lead compound BX-517, a series of C-4' substituted indolinones have been synthesized and evaluated for PDK1 inhibition. Modification at C-4' of the pyrrole afforded potent compounds (7b and 7d) with improved solubility and ADME properties. In this letter, we describe the synthesis, selectivity profile, and pharmacokinetic data of selected compounds.
Islam
Imadul
I
Berlex Biosciences, 2600 Hilltop Dr. Richmond, CA 94804, USA. imadulislam@yahoo.com
Brown
Greg
G
Bryant
Judi
J
Hrvatin
Paul
P
Kochanny
Monica J
MJ
Phillips
Gary B
GB
Yuan
Shendong
S
Adler
Marc
M
Whitlow
Marc
M
Lentz
Dao
D
Polokoff
Mark A
MA
Wu
James
J
Shen
Jun
J
Walters
Janette
J
Ho
Elena
E
Subramanyam
Babu
B
Zhu
Daguang
D
Feldman
Richard I
RI
Arnaiz
Damian O
DO
D064413:3-Phosphoinositide-Dependent Protein Kinases; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
C522901:BX 517; D007211:Indoles; D047428:Protein Kinase Inhibitors; D014508:Urea; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D017346:Protein Serine-Threonine Kinases