- X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
-
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
- Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
-
supporting information
p. 8303 - 8332
(2021/06/30)
-
- Polysubstituted-indazole compounds and application of same as IDO inhibitors
-
The invention discloses polysubstituted-indazole compounds as shown in a formula (I) which is described in the specification, a preparation method for the compounds, and application of the compounds as IDO inhibitors. The compounds provided by the invention can be used for preventing and/or treating a plurality of diseases, such as Alzheimer's disease, cataract, infections related to cellular immune activation, autoimmune diseases, AIDS, cancers, depression, the metabolic disorder of tryptophan or the like.
- -
-
Paragraph 0073; 0081; 0082
(2018/11/04)
-
- Indazole compounds and application thereof to preparation of IDO inhibitors
-
The invention discloses indazole compounds as shown in a formula (i) or (II) which is described in the specification, and a preparation method thereof, and application of the compounds as IDO inhibitors. The compounds provided by the invention can be used for preventing and/or treating a plurality of diseases, such as Alzheimer's disease, cataract, infections related to cellular immune activation,autoimmune diseases, AIDS, cancers, depression, the metabolic disorder of tryptophan or the like.
- -
-
Paragraph 0056; 0058; 0066; 0067
(2018/11/04)
-
- Indazole derivatives for use in the treatment of influenza virus infection
-
The present invention is directed to compounds for use in the treatment or prevention of influenza virus infection.
- -
-
Page/Page column 155; 156
(2016/06/01)
-
- NOVEL COMPOUNDS
-
The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I): and salts thereof. The compounds of the invention are inhibitors of PI3-kinase activity.
- -
-
Page/Page column 85-86
(2011/06/25)
-
- NOVEL COMPOUNDS
-
The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I) and salts thereof. The compounds of the invention are inhibitors of PI3-kinase activity.
- -
-
Page/Page column 79-80
(2009/12/28)
-
- BENZPYRAZOL DERIVATIVES AS INHIBITORS OF PI3 KINASES
-
The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I) and salts thereof. The compounds of the invention are inhibitors of PI3-kinase activity.
- -
-
Page/Page column 149-150
(2009/12/28)
-
- 4-CARBOXAMIDE INDAZOLE DERIVATIVES USEFUL AS INHIBITORS OF P13-KINASES
-
The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I) and salts thereof. The compounds of the invention are inhibitors of P13-kinase activity.
- -
-
Page/Page column 123
(2009/12/28)
-