21630-55-7Relevant academic research and scientific papers
Design of a novel and selective IRAK4 inhibitor using topological water network analysis and molecular modeling approaches
Lee, Myeong Hwi,Balupuri, Anand,Jung, Ye-rim,Choi, Sungwook,Lee, Areum,Sik Cho, Young,Sook Kang, Nam
, (2018)
Protein kinases are deeply involved in immune-related diseases and various cancers. They are a potential target for structure-based drug discovery, since the general structure and characteristics of kinase domains are relatively well-known. However, the ATP binding sites in protein kinases, which serve as target sites, are highly conserved, and thus it is difficult to develop selective kinase inhibitors. To resolve this problem, we performed molecular dynamics simulations on 26 kinases in the aqueous solution, and analyzed topological water networks (TWNs) in their ATP binding sites. Repositioning of a known kinase inhibitor in the ATP binding sites of kinases that exhibited a TWN similar to interleukin-1 receptor-associated kinase 4 (IRAK4) allowed us to identify a hit molecule. Another hit molecule was obtained from a commercial chemical library using pharmacophore-based virtual screening and molecular docking approaches. Pharmacophoric features of the hit molecules were hybridized to design a novel compound that inhibited IRAK4 at low nanomolar levels in the in vitro assay.
Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)
Kinarivala, Nihar,Patel, Ronak,Boustany, Rose-Mary,Al-Ahmad, Abraham,Trippier, Paul C.
, p. 9739 - 9756 (2017/12/26)
Neurodegenerative diseases share certain pathophysiological hallmarks that represent common targets for drug discovery. In particular, dysfunction of proteostasis and the resultant apoptotic death of neurons represent common pathways for pharmacological intervention. A library of aromatic carbamate derivatives based on the clinically available drug flupirtine was synthesized to determine a structure-activity relationship for neuroprotective activity. Several derivatives were identified that possess greater protective effect in human induced pluripotent stem cell-derived neurons, protecting up to 80% of neurons against etoposide-induced apoptosis at concentrations as low as 100 nM. The developed aromatic carbamates possess physicochemical properties desirable for CNS therapeutics. The primary known mechanisms of action of the parent scaffold are not responsible for the observed neuroprotective activity. Herein, we demonstrate that neuroprotective aromatic carbamates function to increase the Bcl-2/Bax ratio to an antiapoptotic state and activate autophagy through induction of beclin 1.
Synthesis and quantitative structure-activity relationships of anticonvulsant 2,3,6-triaminopyridines
Seydel,Schaper,Coats,Cordes
, p. 3016 - 3022 (2007/10/02)
The synthesis of 2,3,6-triaminopyridine derivatives, representing a unique chemical structure for anticonvulsants, is described. The synthetic program was performed (a) to identify more potent analogs, (b) to determine structural properties controlling potency as well as neurotoxicity, and (c) to reduce the requirements for animal testing. As a result, besides other structural properties, the overall molecular lipophilicity (log k', octanol- coated column) explained changes in anticonvulsant potency and neurotoxicity. Mimicking the interaction of the amphiphilic triaminopyridines with biological membranes, NMR experiments in the presence of lecithin vesicles were conducted in order to measure the phospholipid-binding parameter log Δ(1/T2). Replacement of log k' with log Δ(1/T2) in the correlation analysis afforded a more significant equation describing the anticonvulsant activity of 21 derivatives.
2,3-Dihydrospiro[1H-4- and 5-azabenzimidazole-2,1'-cyclohexane] (= spiro[cyclohexane-1,2'(3'H)-1'H-imidazo[4,5-b]pyridine] and spiro[cyclohexane-1,2'(3'H)-1'H-imidazo[4,5-c]pyridine]): Reactions with nucleophiles
Schwoch,Kramer,Neidlein,Suschitzky
, p. 2175 - 2190 (2007/10/02)
The readily available title compounds 4a and 24 react with N-, O-, S-, and C-nucleophiles in presence of MnO2 to give the corresponding mono- or disubstituted 2H-azabenzimidazoles (= azaisobenzimidazoles), e.g., 11-18 and 26a-h, respectively, or 2,3-dihydro-1H-azabenzimidazoles (= dihydro-azabenzimidazoles) such as 9 and 10 and 27 and 28, respectively, by a 1,4- or 1,6-Michael addition (Schemes 2 and 4). The bromo-dihydro-1H-azabenzimidazole 4b lost the Br-atom when treated with piperidine or morpholine yielding the corresponding disubstituted 2H-azabenzimidazole 21 (Scheme 3). Reductive ring opening of the substituted spiro compounds leads to mono- and disubstituted diaminopyridines which are intermediates for fused pyridine ring systems with substituents often not available by conventional routes and of potential pharmaceutical interest (see 32-37). E.g., starting from 4a, a three-step synthesis of the analgesic flupirtine maleate (= ethyl {2-amino-6-[(4-fluorobenzyl)amino]pyridin-3-yl}carbamate maleate = Katadolon; 39) and of its non-fluorinated derivative D-7195 is described. Its analogue 40 was similarly made from the spiro compound 24.
