ABSTRACT
A series of 2'-aminoanilides have been identified which exhibit potent and selective inhibitory activity against the cFMS tyrosine kinase. Initial SAR studies within this series are described which examine aroyl and amino group substitutions, as well as the introduction of hydrophilic substituents on the benzene core. Compound 47 inhibits the isolated enzyme (IC(50)=0.027 microM) and blocks CSF-1-induced proliferation of bone marrow-derived macrophages (IC(50)=0.11 microM) and as such, serves as a lead candidate for further optimization studies.
Subject(s)
Anilides/chemical synthesis , Anilides/pharmacology , Anti-Inflammatory Agents/pharmacology , Piperidines/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Anilides/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Macrophages/drug effects , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
2-Hydroxy-4,6-diamino-[1,3,5]triazines are described which are a novel class of potent inhibitors of the VEGF-R2 (flk-1/KDR) tyrosine kinase. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5]triazin-2-ol (14d) exhibited low nanomolar potency in the in vitro enzyme inhibition assay (IC(50) = 18 nM) and submicromolar inhibitory activity in a KDR-induced MAP kinase autophosphorylation assay in HUVEC cells (IC(50) = 280 nM), and also demonstrated good in vitro selectivity against a panel of growth factor receptor tyrosine kinases. Further, 14d showed antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas with an IC(50) of 1 microM.
Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Thiazoles/chemical synthesis , Triazines/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/chemistry , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Aorta/drug effects , Aorta/physiology , Benzothiazoles , Capillaries/drug effects , Capillaries/physiology , Cell Line , Combinatorial Chemistry Techniques , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Humans , Organ Culture Techniques , Phosphorylation , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Triazines/chemistry , Triazines/pharmacology , Umbilical Veins/cytologyABSTRACT
Monoamides of oxalic acid are of interest as bioisosteric replacements for phosphate groups in the design of new enzyme inhibitors. Here, we have demonstrated the use of oxalic acid as a linker to the Wang resin to synthesize individual or libraries of phosphate biosteres. The highly reactive resin-bound acid chloride reacts with arylamines to yield resin-bound N-aryloxamic acids (oxanilic acids). This methodology is especially useful for the rapid synthesis of 2-(oxalylamino)benzoic acids (OBAs), because it can be utilized for library synthesis and eliminates the intermediate purification step necessary in solution-phase reactions. The products are cleaved off the resin with trifluoroacetic acid in dichloromethane in good yields.
