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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.

Li, Hong-yu; Wang, Yan; Heap, Charles R; King, Chi-Hsin R; Mundla, Sreenivasa R; Voss, Matthew; Clawson, David K; Yan, Lei; Campbell, Robert M; Anderson, Bryan D; Wagner, Jill R; Britt, Karen; Lu, Ku X; McMillen, William T; Yingling, Jonathan M.

J Med Chem ; 49(6): 2138-42, 2006 Mar 23.

Article in English | MEDLINE | ID: mdl-16539403

ABSTRACT

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.

Subject(s)

Benzimidazoles/chemical synthesis , MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Cells, Cultured , Humans , Mice , Mice, Nude , Mink , Protein Structure, Tertiary , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Receptor, Transforming Growth Factor-beta Type I , Structure-Activity Relationship , Xenograft Model Antitumor Assays

ABSTRACT

Subject(s)

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