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: Guo-Bo Li, Shuang Ma, Ling-Ling Yang, Sen Ji, Zhen Fang, Guo Zhang, Li-Jiao Wang, Jie-Min Zhong, Yu Xiong, Jiang-Hong Wang, Shen-Zhen Huang, Lin-Li Li, Rong Xiang, Dawen Niu, Ying-Chun Chen, Sheng-Yong Yang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 59 Issue 18 Pg. 8293-305 (Sep 22 2016) ISSN: 1520-4804 [Electronic] United States
• PMID: 27535613 (Publication Type: Journal Article)

Chemical References

• Pyrazoles
• Pyrimidines
• Urea
• fms-Like Tyrosine Kinase 3

Topics

• Animals
• Disease Models, Animal
• Drug Discovery
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Psoriasis (drug therapy, enzymology, pathology)
• Pyrazoles (chemistry, therapeutic use)
• Pyrimidines (chemistry, therapeutic use)
• Urea (analogs & derivatives, therapeutic use)
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, metabolism)