- Development of Multifunctional Pyrimidinylthiourea Derivatives as Potential Anti-Alzheimer Agents
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Starting from a screening-hit compound, via structure modifications and optimizations, a series of nonfused and nonassembly pyrimidinylthiourea derivatives (2-5) was designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease. Biological activity results demonstrated that compounds 5r and 5t exhibited potent inhibition and excellent selectivity toward acetylcholinesterase (AChE, 5r, IC50 = 0.204 μM, SI > 196; 5t, IC50 = 0.067 μM, SI > 597), specific metal-chelating ability, significant antioxidant effects, modulation of metal-induced Aβ aggregation, inhibition of ROS production by copper redox cycle, low cytotoxicity, and moderate neuroprotection to human neuroblastoma SH-SY5Y cells. Moreover, compound 5r displayed appropriate blood-brain barrier (BBB) permeability both in vitro and in vivo and could improve memory and cognitive function of scopolamine-induced amnesia mice. The multifunctional profiles of 5r and its effectivity in AD mice highlight these structurally distinct pyrimidinylthiourea derivatives as prospective prototypes in the research of innovative multifunctional drugs for Alzheimer's disease.
- Li, Xiaokang,Wang, Huan,Lu, Zhengyu,Zheng, Xinyu,Ni, Wei,Zhu, Jin,Fu, Yan,Lian, Fulin,Zhang, Naixia,Li, Jian,Zhang, Haiyan,Mao, Fei
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- BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia
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The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.
- King, Dalton,Iwuagwu, Christiana,Cook, Jim,McDonald, Ivar M.,Mate, Robert,Zusi, F. Christopher,Hill, Matthew D.,Fang, Haiquan,Zhao, Rulin,Wang, Bei,Easton, Amy E.,Miller, Regina,Post-Munson, Debra,Knox, Ronald J.,Gallagher, Lizbeth,Westphal, Ryan,Molski, Thaddeus,Fan, Jingsong,Clarke, Wendy,Benitex, Yulia,Lentz, Kimberley A.,Denton, Rex,Morgan, Daniel,Zaczek, Robert,Lodge, Nicholas J.,Bristow, Linda J.,Macor, John E.,Olson, Richard E.
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- SUBSTITUTED 6-(1H-PYRAZOL-1-YL)PYRIMIDIN-4-AMINE DERIVATIVES AND USES THEREOF
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The present invention covers substituted 6-(1H-pyrazol-1-yl)pyrimidin-4-amine compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular and renal diseases, as a sole agent or in combination with other active ingredients.
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Page/Page column 234-235
(2018/04/27)
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- Α 7 as intranuclear hydroxynicotinic acetylcholine receptor quinuclidines compd.
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PROBLEM TO BE SOLVED: To provide ligands for the nicotinic α-7 receptor used for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.SOLUTION: The disclosure provides compounds of the specified formula I, including their salts, and compositions and methods using the compounds.
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Paragraph 0737; 0738
(2018/10/03)
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- Synthesis and cytoprotective antiulcer activity of 2- or 4-(1H-pyrazol- 1-yl)pyrimidine derivatives related to mepirizole and dulcerozine
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(1H-Pyrazol-1-yl)-, (1H-imidazol-1-yl)-, and (1H-1,2,4-triazol-1- yl)pyrimidines were prepared and evaluated for cytoprotective antiulcer activity. Among them, 4-methoxy-6-methyl-2-(1H-pyrazol-1-yl)pyrimidine (18) showed potent inhibition of the HCl-ethanol-induced and water-immersion stress-induced ulcers in rats, as well as low acute toxicity.
- Ikeda, Masazumi,Maruyama, Kazumi,Nobuhara, Youichi,Yamada, Toshihiro,Okabe, Susumu
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p. 1700 - 1706
(2007/10/03)
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- Pyrimidine derivatives
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The present invention relates to novel pyrimidine derivatives of the general formula STR1 wherein R1 represents a pyrazolyl, imidazolyl, or triazolyl group, R2 represents hydrogen atom or lower alkyl group, R3 represents a halo, amino, lower alkoxy, pyrazolyl, imidazolyl, triazolyl, piperidinyl, or aryloxy group, one of X or Y represents N and the other of X or Y represents CH, and the salts thereof. These derivatives may be used in the treatment of peptic ulcer disease.
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- SYNTHESES OF NEW PYRAZOLE-DERIVED CHELATING LIGANDS
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The preparations and spectral data for nine new N,N'-chelating ligands (5)-(13), each consisting of a pyrazole group N-linked to an azine or azole, are described.
- Steel, Peter J.,Constable, Edwin C.
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p. 1601 - 1611
(2007/10/02)
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