ABSTRACT
A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Subject(s)
Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Humans , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Subject(s)
Amides/chemistry , Imidazolidines/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/administration & dosage , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Amides/pharmacology , Animals , Cell Line, Tumor , HCT116 Cells , Humans , Imidazolidines/pharmacology , Mice , Protein Kinase Inhibitors/pharmacology , Rats , Vascular Endothelial Growth Factor Receptor-2/metabolism , Xenograft Model Antitumor Assays/methodsABSTRACT
A series of N-benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides targeting co-activator associated arginine methyltransferase 1 (CARM1) have been designed and synthesized. The potency of these inhibitors was influenced by the nature of the heteroaryl fragment with the thiophene analogues being superior to thiazole, pyridine, isoindoline and benzofuran based inhibitors.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Amides/chemistry , Combinatorial Chemistry Techniques , Molecular Structure , Pyrazoles/chemistry , Thiophenes/chemistryABSTRACT
The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.
