ABSTRACT
The inhibition of receptor tyrosine kinases (RTKs) has become a successful approach in the development of anticancer agents. Many potent small-molecule kinase inhibitors have been discovered. We report herein a series of pyrrolo-fused-heterocycle-2-indolinone analogues as inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-Kit. Among them, some pyrrolo-fused six- and seven-membered-heterocycle derivatives such as 9, 15, 23, and 25 are potent inhibitors of VEGFR, PDGFR, and c-Kit both enzymatically (<50 nM) and cellularly (<50 nM). Furthermore, compounds 9 and 25 possess favorable pharmacokinetic profiles and demonstrate good efficacies against human HT-29 cell colon tumor xenografts in nude mice. Further evaluations are in progress.
Subject(s)
Antineoplastic Agents/chemical synthesis , Indoles/chemical synthesis , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Female , Humans , Indoles/pharmacokinetics , Indoles/pharmacology , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
A series of novel azobicyclo[3.3.0]octane derivatives were synthesized and evaluated as dipeptidyl peptidase 4 (DPP-4) inhibitors. The effort resulted in the discovery of inhibitor 2a, which exhibited excellent efficacies in an oral glucose tolerance test. Introduction of methyl group (2j) could prolong the inhibition of serum DPP-4 activity.
