Dihydropyrrolopyrazole transforming growth factor-beta type I receptor kinase domain inhibitors: a novel benzimidazole series with selectivity versus transforming growth factor-beta type II receptor kinase and mixed lineage kinase-7.
Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.
Discovery Chemistry Research and Technology, Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. li_hong-yu@lilly.com
Hong-yu
HY
Li
Yan
Y
Wang
Charles R
CR
Heap
Chi-Hsin R
CH
King
Sreenivasa R
SR
Mundla
Matthew
M
Voss
David K
DK
Clawson
Lei
L
Yan
Robert M
RM
Campbell
Bryan D
BD
Anderson
Jill R
JR
Wagner
Karen
K
Britt
Ku X
KX
Lu
William T
WT
McMillen
Jonathan M
JM
Yingling
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D008907:Mink; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000099151:MAP Kinase Kinase Kinase 7
D001562:Benzimidazoles; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011758:Pyrroles; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C509864:6-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo(1,2-b)pyrazol-3-yl)-1H-benzoimidazole