title: Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model.
abstract: Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Guo-Bo
authors.initials: GB
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.|College of Food and Bioengineering, Xihua University , Chengdu, Sichuan 610039, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.|College of Food and Bioengineering, Xihua University , Chengdu, Sichuan 610039, China.
authors.forename: Li-Jiao
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Jie-Min
authors.initials: JM
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Jiang-Hong
authors.initials: JH
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Shen-Zhen
authors.initials: SZ
authors.lastname: Huang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.affiliation: Department of Clinical Medicine, School of Medicine, Nankai University , Tianjin, 300071, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Dawen
authors.initials: D
authors.lastname: Niu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu, Sichuan 610041, China.
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University/Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D055808:Drug Discovery; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011565:Psoriasis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011720:Pyrazoles / Q000737:chemistry / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use*; D014508:Urea / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D014508:Urea; D051941:fms-Like Tyrosine Kinase 3