- 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
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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
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p. 8303 - 8332
(2021/06/30)
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- EZH2 INHIBITOR AND PHARMACEUTICALLY ACCEPTABLE SALTS AND POLYMORPHIC SUBSTANCES THEREOF, AND APPLICATION OF EZH2 INHIBITOR
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The present invention provides an EZH2 inhibitor and pharmaceutically acceptable salts and polymorphic substances thereof, and application of the EZH2 inhibitor. Specifically, the present invention provides N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)m
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- TYK2 INHIBITORS AND USES THEREOF
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Described herein are compounds that are useful in treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
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- 4,5,6-TRI-SUBSTITUTED INDAZOLES DERIVATIVES, PREPARATION THEREOF, AND USE THEREOF IN MEDICINES
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Provided are 4,5,6-tri-substituted indazoles derivatives, a preparation method therefor, and a use thereof in medicines. Specifically, provided are compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof
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- Orally active zwitterionic factor Xa inhibitors with long duration of action
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We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administrat
- Mochizuki, Akiyoshi,Nagata, Tsutomu,Kanno, Hideyuki,Takano, Daisuke,Kishida, Masamichi,Suzuki, Makoto,Ohta, Toshiharu
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p. 7337 - 7343
(2012/02/04)
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- Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics
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Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays.
- Charrier, Nicolas,Clarke, Brian,Cutler, Leanne,Demont, Emmanuel,Dingwall, Colin,Dunsdon, Rachel,Hawkins, Julie,Howes, Colin,Hubbard, Julia,Hussain, Ishrut,Maile, Graham,Matico, Rosalie,Mosley, Julie,Naylor, Alan,O'Brien, Alistair,Redshaw, Sally,Rowland, Paul,Soleil, Virginie,Smith, Kathrine J.,Sweitzer, Sharon,Theobald, Pam,Vesey, David,Walter, Daryl S.,Wayne, Gareth
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scheme or table
p. 3664 - 3668
(2010/03/24)
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- HYDROXYETHYLAMINE DERIVATIVES FOR THE TREATMENT OF ALZHEIMER'S DISEASE
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The present invention relates to novel hydroxyethylamine compounds of formula (I): (I) having Asp2 (-secretase, BACE1 or Memapsin) inhibitory activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases characterised by elevated-amyloid levels or-amyloid deposits, particularly Alzheimer's disease.
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