ABSTRACT
Preclinical investigations and early clinical trials suggest that FLT3 inhibitors are a viable therapy for acute myeloid leukemia. However, early clinical data have been underwhelming due to incomplete inhibition of FLT3. We have developed 3-phenyl-1H-5-pyrazolylamine as an efficient template for kinase inhibitors. Structure-activity relationships led to the discovery of sulfonamide, carbamate and urea series of FLT3 inhibitors. Previous studies showed that the sulfonamide 4 and carbamate 5 series were potent and selective FLT3 inhibitors with good in vivo efficacy. Herein, we describe the urea series, which we found to be potent inhibitors of FLT3 and VEGFR2. Some inhibited growth of FLT3-mutated MOLM-13 cells more strongly than the FLT3 inhibitors sorafenib (2) and ABT-869 (3). In preliminary in vivo toxicity studies of the four most active compounds, 10f was found to be the least toxic. A further in vivo efficacy study demonstrated that 10f achieved complete tumor regression in a higher proportion of MOLM-13 xenograft mice than 4 and 5 (70% vs 10% and 40%). These results show that compound 10f possesses improved pharmacologic and selectivity profiles and could be more effective than previously disclosed FLT3 inhibitors in the treatment of acute myeloid leukemia.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzamides/chemical synthesis , Benzamides/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Urea/analogs & derivatives , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzamides/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Discovery , Humans , Inhibitory Concentration 50 , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/pathology , Mice , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Sensitivity and Specificity , Structure-Activity Relationship , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacology , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3/chemistryABSTRACT
A new class of FLT3 inhibitors has been identified based on the 3-phenyl-1H-5-pyrazolylamine scaffold. The structure-activity relationships led to the discovery of two carbamate series, and some potent compounds within these two series exhibited better growth inhibition of FLT3-mutated MOLM-13 cells than FLT3 inhibitors sorafenib (2) and ABT-869 (3). In particular, compound 8d exhibited the ability to regress tumors in mouse xenograft model using MOLM-13 cells.
Subject(s)
Amines/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Amines/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Mice , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A novel series of N-linked ß-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(ß-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
