Identification of novel inhibitors of the transforming growth factor β1 (TGF-β1) type 1 receptor (ALK5)

被引：279

作者：

Callahan, JF

Burgess, JL

Fornwald, JA

Gaster, LM

Harling, JD

Harrington, FP

Heer, J

Kwon, C

Lehr, R

Mathur, A

Olson, BA

Weinstock, J

Laping, NJ

机构：

[1] GlaxoSmithKline Pharmaceut, Dept Med Chem, Collegeville, PA 19426 USA

[2] GlaxoSmithKline Pharmaceut, Dept Med Chem, King Of Prussia, PA 19406 USA

[3] GlaxoSmithKline Pharmaceut, Dept Renal Pharmacol, King Of Prussia, PA 19406 USA

[4] GlaxoSmithKline Pharmaceut, Dept Prot Biochem, King Of Prussia, PA 19406 USA

[5] GlaxoSmithKline Pharmaceut, Dept Gene Express Sci, King Of Prussia, PA 19406 USA

[6] Dept Med Chem, Harlow CM19 5AD, Essex, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 05期

关键词：

D O I：

10.1021/jm010493y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.

引用

页码：999 / 1001

页数：3

共 16 条

[1] EFFECTS OF TRANSFORMING GROWTH FACTOR-BETA-1 ON THE EXTRACELLULAR-MATRIX AND CYTOSKELETON OF CULTURED ASTROCYTES
BAGHDASSARIAN, D
TORUDELBAUFFE, D
GAVARET, JM
PIERRE, M
[J]. GLIA, 1993, 7 (03) : 193 - 202
[2] 1-substituted 4-aryl-5-pyridinylimidazoles: A new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency
Boehm, JC
Smietana, JM
Sorenson, ME
Garigipati, RS
Gallagher, TF
Sheldrake, PL
Bradbeer, J
Badger, AM
Laydon, JT
Lee, JC
Hillegass, LM
Griswold, DE
Breton, JJ
ChabotFletcher, MC
Adams, JL
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (20) : 3929 - 3937
[3] New inhibitors of p38 kinase
Boehm, JC
Adams, JL
[J]. EXPERT OPINION ON THERAPEUTIC PATENTS, 2000, 10 (01) : 25 - 37
[4] PHOSPHORYLATION-DEPENDENT INTERACTION OF THE CYTOPLASMIC DOMAINS OF THE TYPE-I AND TYPE-II TRANSFORMING GROWTH-FACTOR-BETA RECEPTORS
CHEN, RH
MOSES, HL
MARUOKA, EM
DERYNCK, R
KAWABATA, M
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (20) : 12235 - 12241
[5] TGF-beta receptor signaling
Derynck, R
Feng, XH
[J]. BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 1997, 1333 (02): : F105 - F150
[6] Conversion of SB 203580-insensitive MBP kinase family members to drug-sensitive forms by a single amino-acid substitution
Eyers, PA
Craxton, M
Morrice, N
Cohen, P
Goedert, M
[J]. CHEMISTRY & BIOLOGY, 1998, 5 (06): : 321 - 328
[7] Regulation of stress-induced cytokine production by pyridinylimidazoles; Inhibition of CSBP kinase
Gallagher, TF
Seibel, GL
Kassis, S
Laydon, JT
Blumenthal, MJ
Lee, JC
Lee, D
Boehm, JC
FierThompson, SM
Abt, JW
Soreson, ME
Smietana, JM
Hall, RF
Garigipati, RS
Bender, PE
Erhard, KF
Krog, AJ
Hofmann, GA
Sheldrake, PL
McDonnell, PC
Kumar, S
Young, PR
Adams, JL
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 1997, 5 (01) : 49 - 64
[8] 2,4,5-TRIARYLIMIDAZOLE INHIBITORS OF IL-1 BIOSYNTHESIS
GALLAGHER, TF
FIERTHOMPSON, SM
GARIGIPATI, RS
SORENSON, ME
SMIETANA, JM
LEE, D
BENDER, PE
LEE, JC
LAYDON, JT
GRISWOLD, DE
CHABOTFLETCHER, MC
BRETON, JJ
ADAMS, JL
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1995, 5 (11) : 1171 - 1176
[9] TGF-beta signalling from cell membrane to nucleus through SMAD proteins
Heldin, CH
Miyazono, K
tenDijke, P
[J]. NATURE, 1997, 390 (6659) : 465 - 471
[10] Hepatocyte growth factor: A regulator of extracellular matrix genes in mouse mesangial cells
Laping, NJ
Olson, BA
Ho, T
Ziyadeh, FN
Albrightson, CR
[J]. BIOCHEMICAL PHARMACOLOGY, 2000, 59 (07) : 847 - 853

← 1 2 →