- Decarboxylative Bromination of Heteroarenes: Initial Mechanistic Insights
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After an initial report from our laboratory describing metal-free decarboxylative halogenation of various azaheteroarenes, we set out to investigate the possible mechanism by which this chemistry occurs. Evidence from this mechanistic investigation sugges
- Patel, Pritesh R.,Henderson, Scott H.,Roe, Mark S.,Honey, Mark A.
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- Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors
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Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.
- Ashall-Kelly, Alexander,Bennett, James,Elkins, Jonathan M.,Fedorov, Oleg,Godoi, Paulo H.,Hanley, Marcus T.,Henderson, Scott H.,Hopkins Navratilova, Iva,Robinson, Sean,Ruela De Sousa, Roberta,Sorrell, Fiona,Walter, Daryl S.,Ward, Simon E.
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p. 11709 - 11728
(2021/08/24)
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- Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5- b]pyridazines for the Treatment of Human African Trypanosomiasis
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From a high-throughput screen of 42 44 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compounds against h
- Tear, Westley F.,Bag, Seema,Diaz-Gonzalez, Rosario,Ceballos-Pérez, Gloria,Rojas-Barros, Domingo I.,Cordon-Obras, Carlos,Pérez-Moreno, Guiomar,García-Hernández, Raquel,Martinez-Martinez, Maria Santos,Ruiz-Perez, Luis Miguel,Gamarro, Francisco,Gonzalez Pacanowska, Dolores,Caffrey, Conor R.,Ferrins, Lori,Manzano, Pilar,Navarro, Miguel,Pollastri, Michael P.
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p. 756 - 783
(2020/02/04)
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- DIARYL KETIMINE DERIVATIVE HAVING ANTAGONISM AGAINST MELANIN-CONCENTRATING HORMONE RECEPTOR
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[Problems] To provide an antagonist of a melanin-concentrating hormone receptor, which is useful as a medicine for a central nervous system disease, a cardiovascular disease or a metabolic disease. [Means for Solving Problems] The antagonist comprises, as an active ingredient, a compound represented by the formula (I) wherein R1a and R1b independently represent a hydrogen atom or a C1-6 alkyl group; R2a, R2b, R3a and R3b independently represent a hydrogen atom, a C1-6 alkyl group, or the like; Y represents H or —OH; Z represents —OR8, or the like; R8 represents a hydrogen atom, a C1-6 alkyl group which may have a substituent, or the like; R9a and R9b independently represent a hydrogen atom, a C1-6 alkyl group, or the like; Ar1 represents an aromatic carbon ring group, or an aromatic heteroring group; Ar2 represents a group produced by removing two hydrogen atoms from an aromatic carbon ring, or the like; and the ring group A represents an unsaturated heteroring group.
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Page/Page column 26
(2010/12/31)
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