title: Structure based design and syntheses of amino-1H-pyrazole amide derivatives as selective Raf kinase inhibitors in melanoma cells.
abstract: The synthesis of a novel series of N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl amide derivatives 6a-o, 7a-s and their antiproliferative activities against A375P melanoma cell line were described. Most compounds showed competitive antiproliferative activities to sorafenib, the reference standard. Among them, N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido)-2-methylbenzamide 7c exhibited potent activities (GI(50)=0.27 μM). Especially, 7c was found to be a potent and selective B-Raf V600E and C-Raf inhibitor (IC(50)=0.26 μM, IC(50)=0.11 μM, respectively), showing a possibility as melanoma therapeutics.
authors.affiliation: Department of Pharmacy, College of Pharmacy, Hanyang University, 1271 Sa 3-Dong, Sangnok-gu, Ansan-si, Gyunggi-do 426-791, South Korea.
authors.forename: Mi-hyun
authors.initials: MH
authors.lastname: Kim
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.forename: Hana
authors.initials: H
authors.lastname: Yu
authors.forename: Hwan
authors.initials: H
authors.lastname: Kim
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Yoo
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: Jung-Mi
authors.initials: JM
authors.lastname: Hah
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D009536:Niacinamide; C031280:pyrazole; D000077157:Sorafenib; D048490:raf Kinases