1. Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).
- Author
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Lin WH, Hsu JT, Hsieh SY, Chen CT, Song JS, Yen SC, Hsu T, Lu CT, Chen CH, Chou LH, Yang YN, Chiu CH, Chen CP, Tseng YJ, Yen KJ, Yeh CF, Chao YS, Yeh TK, and Jiaang WT
- Subjects
- 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 chemistry, 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
- 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., (Copyright © 2013. Published by Elsevier Ltd.)
- Published
- 2013
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