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Discovery of the novel potent and selective FLT3 inhibitor 1-{5-[7-(3- morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and its anti-acute myeloid leukemia (AML) activities in vitro and in vivo.
- Source :
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Journal of medicinal chemistry [J Med Chem] 2012 Apr 26; Vol. 55 (8), pp. 3852-66. Date of Electronic Publication: 2012 Apr 06. - Publication Year :
- 2012
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Abstract
- Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Cell Line, Tumor
Drug Design
Humans
Mice
Phenylurea Compounds chemical synthesis
Quinazolines chemical synthesis
Structure-Activity Relationship
Thiadiazoles chemical synthesis
Xenograft Model Antitumor Assays
Antineoplastic Agents therapeutic use
Leukemia, Myeloid, Acute drug therapy
Phenylurea Compounds therapeutic use
Quinazolines therapeutic use
Thiadiazoles therapeutic use
fms-Like Tyrosine Kinase 3 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22452518
- Full Text :
- https://doi.org/10.1021/jm300042x