302963-94-6Relevant articles and documents
Synthesis of GluN2A-selective NMDA receptor antagonists with an electron-rich aromatic B-ring
Rajan, Remya,Schepmann, Dirk,Schreiber, Julian A.,Seebohm, Guiscard,Wünsch, Bernhard
, (2020/11/13)
Glutamatergic N-Methyl-D-aspartate (NMDA) receptors are heterotetrameric ion channels that can be comprised of different subunits. GluN2A subunit-containing NMDA receptors are associated with diseases like anxiety, depression, and schizophrenia. However,
ARYLUREA DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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Page/Page column 52, (2008/06/13)
A compound of formula (I), wherein substituents are as given above, useful in the treatment of a disease mediated by the action of CCR3, in particular inflammatory or obstructive airway diseases.
2-Aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6- [4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1, 3-thiazole-5-carboxamide (Dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor
Das, Jagabandhu,Chen, Ping,Norris, Derek,Padmanabha, Ramesh,Lin, James,Moquin, Robert V.,Shen, Zhongqi,Cook, Lynda S.,Doweyko, Arthur M.,Pitt, Sidney,Pang, Suhong,Shen, Ding Ren,Fang, Qiong,De Fex, Henry F.,McIntyre, Kim W.,Shuster, David J.,Gillooly, Kathleen M.,Behnia, Kamelia,Schieven, Gary L.,Wityak, John,Barrish, Joel C.
, p. 6819 - 6832 (2007/10/03)
2-Aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 ～ 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFα production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Cyclic protein tyrosine kinase inhibitors
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Page 20, (2010/02/06)
Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.
Discovery and initial SAR of 2-amino-5-carboxamidothiazoles as inhibitors of the Src-family kinase p56Lck
Wityak, John,Das, Jagabandhu,Moquin, Robert V.,Shen, Zhongqi,Lin, James,Chen, Ping,Doweyko, Arthur M.,Pitt, Sidney,Pang, Suhong,Shen, Ding Ren,Fang, Qiong,De Fex, Henry F.,Schieven, Gary L.,Kanner, Steven B.,Barrish, Joel C.
, p. 4007 - 4010 (2007/10/03)
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
Alternative heterocycles for DNA recognition: An N-methylpyrazole/N-methylpyrrole pair specifies for A·T/T·A base pairs
Nguyen, Doan H.,Szewczyk, Jason W.,Baird, Eldon E.,Dervan, Peter B.
, p. 7 - 17 (2007/10/03)
Side-by-side pairs of three five-membered rings, N-methylpyrrole (Py), N-methylimidazole (Im), and N-methylhydroxypyrrole (Hp), have been demonstrated to distinguish each of the four Watson-Crick base pairs in the minor groove of DNA. However, not all DNA sequences targeted by these pairing rules achieve affinities and specificities comparable to DNA binding proteins. We have initiated a search for new heterocycles which can expand the sequence repetoire currently available. Two heterocyclic aromatic amino acids, N-methylpyrazole (Pz) and 4-methylthiazole (Th), were incorporated into a single position of an eight-ring polyamide of sequence ImImXPy-γ-ImPyPyPy-β-Dp to examine the modulation of affinity and specificity for DNA binding by a Pz/Py pair and/or a Th/Py pair. The X/Py pairings Pz/Py and Th/Py were evaluated by quantitative DNase I footprint titrations on a DNA fragment with the four sites 5′-TGGNCA-3′ (N=T, A, G, C). The Pz/Py pair binds T·A and A·T with similar affinity to a Py/Py pair but with improved specificity, disfavoring both G·C and C·G by about 100-fold. The Th/Py pair binds poorly to all four Watson-Crick base pairs. These results demonstrate that in some instances new heterocyclic aromatic amino acid pairs can be incorporated into imidazole-pyrrole polyamides to mimic the DNA specificity of Py/Py pairs which may be relevant as biological criteria in animal studies become important.
