- 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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- Compound, preparation method thereof, pharmaceutical composition and application of compound
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The invention discloses a compound, a preparation method thereof, a pharmaceutical composition and application of the compound. The compound I, and a stereoisomer or a pharmacologically acceptable salt thereof can serve as a CDK7 kinase inhibitor, are high in inhibition activity, and can be used for treatment of various malignant tumors.
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- COMPOUNDS AND USE FOR TREATING CANCER
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The present invention relates to certain 2,4-disubstituted quinoline derivatives, to their therapy, as well as to pharmaceutical compositions comprising said compounds. More specifically the invention relates to certain 2,4-disubstituted quinoline derivatives or pharmaceutical compositions comprising said compounds for the treatment of cancers characterized by overactive Ras and/or Rac or signalling pathway.
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- Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
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The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.
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Paragraph 0209; 0428; 0431; 0432
(2016/10/20)
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- SUBSTITUTED ADIPIC ACID AMIDES AND USES THEREOF
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A is a five to eight membered monocyclic or a nine to twelve membered bicyclic heterocyclic ring, as further defined herein; Y is S, CH2, or CH; Z is CH or N; R7 and R9 are hydrogen or (C1-C6)alkyl; R2 is (C1 C6)alkoxy, OH, CN, (C1-C6)alkyl, halogen, or CF3; r and s are 0, 1, or 2; and R1 and R3 are as further defined herein. These compounds are agonists, partial agonists and/or modulators of the NPY4 receptor and may be used for the treatment and prophylaxis of obesity, food intake, and other diseases and conditions modulated by the NPY4 receptor.
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Page/Page column 123
(2012/10/07)
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- An expedient total synthesis of optically active piperidine and indolizidine alkaloids (-)-β-conhydrine and (-)-lentiginosine
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Attempts directed toward the stereocontroled total synthesis of piperidine and indolizidine alkaloids resulted in the synthesis of (-)-β-conhydrine 1 and (-)-lentiginosine 3. The synthesis of 1 and 3 were developed from protected d-mannitol as the chiral
- Kamal, Ahmed,Vangala, Saidi Reddy
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p. 1341 - 1347
(2011/04/12)
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- Dynamic resolution of N-Boc-2-lithiopiperidine
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Dynamic thermodynamic resolution of N-Boc-2-lithiopiperidine is possible using a chiral ligand; the two enantiomers of this organolithium can be resolved with selectivities of up to 85: 15 from a selection of 26 chiral diamino-alkoxide ligands screened. The Royal Society of Chemistry.
- Coldham, Iain,Raimbault, Sophie,Chovatia, Praful T.,Patel, Jignesh J.,Leonori, Daniele,Sheikh, Nadeem S.,Whittaker, David T. E.
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experimental part
p. 4174 - 4176
(2009/03/11)
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- TETRAZOLE DERIVATIVES AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
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The present invention relates to new compounds of formula (I) wherein Y1 and Y2 selected from the group consisting of hydrogen, halogen atom, C1-4 alkyl, C1-4 alkoxy or cyano group, X is oxygen or two hydrogen a
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Page/Page column 31
(2008/06/13)
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- MGLUR5 MODULATORS II
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The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
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Page/Page column 10
(2008/06/13)
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- MGluR5 modulators I
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The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
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Page/Page column 11
(2008/06/13)
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- A new general access to either type of securinega alkaloids: Synthesis of securinine and (-)-allonorsecurinine
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Matrix presented. The syntheses of securinine and (-)-allonorsecurinine have been achieved starting from easily available α-amino acid derivatives and using as key steps a RCM and a Heck reaction for the formation of rings D and C, respectively.
- Alibes, Ramon,Ballbe, Marta,Busque, Felix,De March, Pedro,Elias, Laia,Figueredo, Marta,Font, Josep
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p. 1813 - 1816
(2007/10/03)
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- Synthesis and activity of 3-pyridylamine ligands at central nicotinic receptors
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A series of thirty 2-(3-pyridylaminomethyl)azetidine, pyrrolidine and piperidine analogues as nicotinic acetylcholine receptor (nAChR) ligands was explored. In general, pyrrolidinyl and many azetidinyl compounds were found to bind with enhanced affinity relative to the piperidines. In the three series, the parallel structural changes (stereochemistry, N-methylation and/or chloro substitution) do not consistently lead to parallel shifts in affinity. The more active compounds (K(i) affinity values ranging from 8.9 to 90 nM) were about as analgesic as nicotine in a tail-flick assay in mice after subcutaneous injections. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Balboni, Gianfranco,Marastoni, Mauro,Merighi, Stefania,Borea, Pier Andrea,Tomatis, Roberto
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p. 979 - 988
(2007/10/03)
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- Total synthesis of (+)-aloperine. Use of a nitrogen-bound silicon tether in an intramolecular diels-alder reaction
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Enantioselective total syntheses of aloperine (1), N-methylaloperine (2), and N-allylaloperine (3) are reported. The central element of the synthetic strategy is an intramolecular Diels-Alder reaction in which the cycloaddends are tethered by a N-silylamine linkage. The total synthesis of 1 proceeds from commercially available 3-hydroxypiperidine hydrochloride (54) and (R)-pipecolinic acid (35) by way of nine isolated and purified intermediates. The synthesis is sufficiently efficient that gram quantities of (+)-aloperine (1) can be readily prepared. Early exploratory studies also introduced a convenient method for tethering cycloaddition partners with a sulfonamide unit to realize the intramolecular Diels-Alder cycloaddition of a vinylsulfonamide: 45 → 46.
- Brosius, Arthur D.,Overman, Larry E.,Schwink, Lothar
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p. 700 - 709
(2007/10/03)
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- Synthesis and in Vitro Characterization of Novel Amino Terminally Modified Oxotremorine Derivatives for Brain Muscarinic Receptors
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A series of novel 2-substituted acetylenic pyrrolidines and piperidines related to oxotremorine (1) were prepared and evaluated in vitro as muscarinic cholinergic agents at brain M1 and M2 receptors.One analogue, 3-(2-oxo-1-pyrrolidinyl)-1--1-propyne hydrogen oxalate (6a), was found to be a partial agonist producing a PI hydrolysis response at cortical M1 receptors approximately 3-fold larger than that produced by 1.The intrinsic activity profile of 6a at brain muscarinic receptors is similar to those of azetidine oxo analogue 2 and dimethylamino oxo analogue (3).All three compounds are partial M1 agonists and full M2 agonists; however, the profile of 6a in binding studies is significantly different.While 2 and 3 exhibit large M2 selectivities ranging between 8-fold to several hundred-fold, the binding profile of 6a shows almost no subtype selectivity.
- Garvey, David S.,Wasicak, James T.,Chung, John Y.-L.,Shue, Youe-Kong,Carrera, George M.,et al.
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p. 1550 - 1557
(2007/10/02)
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