- Structure-based drug design of novel, potent, and selective azabenzimidazoles (ABI) as ATR inhibitors
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Compound 13 was discovered through morphing of the ATR biochemical HTS hit 1. The ABI series was potent and selective for ATR. Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition. DMPK experiments established that CYP P450 and AO metabolism in conjunction with Pgp and BCRP efflux were major causative mechanisms for the observed PK. The series also harbored the CYP3A4 TDI liability driven by the presence of both a morpholine and an indole moiety. Incorporation of an adjacent fluorine or nitrogen into the 6-azaindole addressed many of the various medicinal chemistry issues encountered. (Chemical Presented).
- Barsanti, Paul A.,Pan, Yue,Lu, Yipin,Jain, Rama,Cox, Matthew,Aversa, Robert J.,Dillon, Michael P.,Elling, Robert,Hu, Cheng,Jin, Xianming,Knapp, Mark,Lan, Jiong,Ramurthy, Savithri,Rudewicz, Patrick,Setti, Lina,Subramanian, Sharadha,Mathur, Michelle,Taricani, Lorena,Thomas, George,Xiao, Linda,Yue, Qin
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Read Online
- New approach to synthesize symmetrical and unsymmetrical 6-(N-Alkyl(Aryl)amino)-and 6-(N, N-dialkyl(Aryl)amino)-2,4-bis(Alkyl(Aryl)Thio) pyrimidines as anti-platelet agents
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A new and straightforward procedure has been developed for the preparation of symmetrical and unsymmetrical 6-(N-alkyl(aryl)amino)-and 6-(N,N- bisalkyl(aryl)amino)-2,4-bis(alkyl(aryl)thio)pyrimidines. The two identical or different alkylthio groups were s
- Liu, Guocheng,Xu, Jiaxi,Yu, Mingwu,Chen, Ning,Zhang, Si,Ding, Zhongren,Du, Hongguang
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scheme or table
p. 650 - 659
(2012/06/01)
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- Novel synthesis approach and antiplatelet activity evaluation of 6-alkylamino-2,4-dialkyl(aryl)thiopyrimidines
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A new and efficient procedure has been designed for the preparation of 6-alkylamino-2,4-dialkyl(aryl)thiopyrimidines. The first alkylthio group was introduced into the pyrimidine ring by S-alkylation. The introduction of the second one was successfully ac
- Liu, Guocheng,Xu, Jiaxi,Park, Ki Chul,Chen, Ning,Zhang, Si,Ding, Zhongren,Wang, Feng,Du, Hongguang
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experimental part
p. 5156 - 5161
(2011/07/31)
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- THERAPEUTIC METHODS AND COMPOSITIONS INVOLVING ALLOSTERIC KINASE INHIBITION
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The present invention is directed to methods and compositions for suppressing lymphangiogenesis, angiogenesis and/or tumor growth. The methods comprise contacting the tumor with a compound that (i) stabilizes a protein kinase in the inactive state and (ii
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Page/Page column 100-101
(2011/09/14)
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- Antitumor studies. Part 3: Design, synthesis, antitumor activity, and molecular docking study of novel 2-methylthio-, 2-amino-, and 2-(N-substituted amino)-10-alkyl-2-deoxo-5-deazaflavins
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Various novel 10-alkyl-2-deoxo-2-methylthio-5-deazaflavins have been synthesized by reaction of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones with Vilsmeier reagent. The similar 2-(N-substituted amino) derivatives were prepared by nucleophilic replacement reaction of the 2-methylthio moiety by appropriate amines. The 2-oxo derivatives (i.e., 5-deazaflavins) were obtained by acidic hydrolysis of the 2-methylthio derivatives. The antitumor activities against CCRF-HSB-2 and KB cells and the antiviral activities against HSV-1 and HSV-2 have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK has been done for lead optimization of these compounds as potential PTK inhibitors. Whereas, the designed 2-deoxo-5-deazaflavins connected with amino acids at the 2-position exhibited the good binding affinities into PTK with more hydrogen bonds.
- Ali, Hamed I.,Ashida, Noriyuki,Nagamatsu, Tomohisa
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p. 6336 - 6352
(2008/03/18)
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- AMINOTHIAZOLE DERIVATIVES AS INHIBITORS OF MARK
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Compounds of formula (I): inhibit microtubule affinity regulating kinase (MARK) and therefore find use in treatment of neurodegenerative diseases associated with hyperphosphorylation of tau.
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Page/Page column 25
(2008/06/13)
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- Substituted heterocyclic compounds and methods of use
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The present invention relates to triazolopyrimidines, imidazolopyrimidines and derivatives thereof, and pharmaceutically acceptable salts thereof. Also included is a method of treatment of inflammation, rheumatoid arthritis, Pagets disease, osteoporosis,
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Page/Page column 20
(2008/06/13)
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- Solid-phase synthesis of 2,4,6-triaminopyrimidines
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Substituted pyrimidines are an important class of kinase inhibitors. We therefore developed a synthetic route suitable for the solid-phase synthesis of 2,4,6-triaminopyrimidines through displacement reactions on deactivated pyrimidines. Functionalising th
- Guillier, Fabrice,Roussel, Patrick,Moser, Heinz,Kane, Peter,Bradley, Mark
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p. 3450 - 3458
(2007/10/03)
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- Antifungal method, formulations and compounds
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Some known 4-amino-6-chloro-5-(H or CH3)-2-(methylthio or methoxy)pyrimidines have been found to be active against fungi. The compounds are systemically active in plants, that is to say, the compounds are carried by plant juices to sites of inf
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