ABSTRACT
In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrroles/pharmacology , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Biological Availability , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Design , Humans , Mice , Mice, Nude , Models, Molecular , Molecular Conformation , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Rats , Receptor, Transforming Growth Factor-beta Type I , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
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.
