ABSTRACT
A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.
Subject(s)
Insulin Resistance , PPAR delta/agonists , Fluorescence Resonance Energy Transfer , Structure-Activity RelationshipABSTRACT
Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.
Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Humans , Mice , Protein Kinase Inhibitors/therapeutic use , Structure-Activity RelationshipABSTRACT
Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
