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.
MeSH terms
-
Administration, Oral
-
Animals
-
Antineoplastic Agents / administration & dosage*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Biological Availability
-
Cell Proliferation / drug effects
-
Crystallography, X-Ray
-
Drug Design
-
Humans
-
Mice
-
Mice, Nude
-
Models, Molecular
-
Molecular Conformation
-
Protein Kinase Inhibitors / administration & dosage*
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology*
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Pyrazoles / chemical synthesis
-
Pyrazoles / chemistry
-
Pyrazoles / pharmacology*
-
Pyrroles / chemical synthesis
-
Pyrroles / chemistry
-
Pyrroles / pharmacology*
-
Rats
-
Receptor, Transforming Growth Factor-beta Type I
-
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
-
Stereoisomerism
-
Structure-Activity Relationship
-
Xenograft Model Antitumor Assays
Substances
-
Antineoplastic Agents
-
LY2109761
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Pyrroles
-
Receptors, Transforming Growth Factor beta
-
Protein Serine-Threonine Kinases
-
Receptor, Transforming Growth Factor-beta Type I
-
Tgfbr1 protein, rat