title: Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).
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.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Rd., Zhunan Town, Miaoli Country 350, Taiwan, ROC.
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Hsieh
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Yen
authors.forename: Tsu
authors.initials: T
authors.lastname: Hsu
authors.forename: Cheng-Tai
authors.initials: CT
authors.lastname: Lu
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Chou
authors.forename: Yung-Ning
authors.initials: YN
authors.lastname: Yang
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Chiu
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chen
authors.forename: Ya-Ju
authors.initials: YJ
authors.lastname: Tseng
authors.forename: Kuei-Jung
authors.initials: KJ
authors.lastname: Yen
authors.forename: Ching-Fang
authors.initials: CF
authors.lastname: Yeh
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C584669:N1-(3-(4-(((5-(tert-butyl)-3-isoxazolyl)aminocarbonyl)amino)methylphenyl)-1H-5-pyrazolyl)-4-(2-morpholinoethoxy)benzamide; D047428:Protein Kinase Inhibitors; D014508:Urea; D051941:fms-Like Tyrosine Kinase 3