383870-96-0Relevant articles and documents
Design, synthesis and biological evaluation of Tozadenant analogues as adenosine A2A receptor ligands
Renk, Dana R.,Skraban, Marcel,Bier, Dirk,Schulze, Annette,Wabbals, Erika,Wedekind, Franziska,Neumaier, Felix,Neumaier, Bernd,Holschbach, Marcus
, (2021/02/09)
With the aim to obtain potent adenosine A2A receptor (A2AR) ligands, a series of eighteen derivatives of 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide (SYN-115, Tozadenant) were designed and synthesized. The target compounds were obtained by a chemical building block principle that involved reaction of the appropriate aminobenzothiazole phenyl carbamates with either commercially available or readily synthesized functionalized piperidines. Their affinity and subtype selectivity with regard to human adenosine A1-and A2A receptors were determined using radioligand binding assays. Ki values for human A2AR ranged from 2.4 to 38 nM, with more than 120-fold selectivity over A1 receptors for all evaluated compounds except 13k which had a Ki of 361 nM and 18-fold selectivity. The most potent fluorine-containing derivatives 13e, 13g and 13l exhibited Ki values of 4.9 nM, 3.6 nM and 2.8 nM for the human A2AR. Interestingly, the corresponding values for rat A2AR were found to be four to five times higher. Their binding to A2AR was further confirmed by radiolabeling with 18F and in vitro autoradiography in rat brain slices, which showed almost exclusive striatal binding and complete displacement by the A2AR antagonist ZM 241385. We conclude that these compounds represent potential candidates for the visualization of the A2A receptor and open pathways to novel therapeutic treatments of neurodegenerative disorders or cancer.
Discovery of novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9
Gao, Jiadi,Fang, Cheng,Xiao, Zhiyan,Huang, Li,Chen, Chin-Ho,Wang, Li-Ting,Lee, Kuo-Hsiung
, p. 444 - 454 (2015/03/18)
Based on a 3D-QSAR pharmacophore derived from a diverse set of known cyclin-dependent kinase 9 (CDK9) inhibitors and a composite pharmacophore extracted from the complex structure of flavopiridol (FVP)-CDK9, thirty novel 5-fluoro-N2,N4-diphenylpyrimidine-2,4-diamine derivatives were designed and synthesized. Initial tests against four tumor cell lines with the sulforhodamine B (SRB) assay identified a series of potent compounds with GI50 values at a lower micromolar or submicromolar level. Most of the highly cytotoxic compounds exhibited potent inhibitory activities against both CDK2/cyclin E1 and CDK9/cyclin T1. Notably, inhibitions against the two enzymes were generally correlated well with the cytotoxicity of these compounds. Appreciable inhibition was also observed for selected compounds in the anti-HIV-1 assay. Docking studies on compounds 6d and 9g provided conducive clues to further structural optimization. This journal is
DIKETOPIPERAZINE DERIVATIVES AS P2X7 MODULATORS
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Page/Page column 84-85, (2010/11/17)
The invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: (I) wherein: A represents an aryl, heteroaryl or heterocyclyl group; and any ring or ring system of said aryl or heteroaryl is optionally substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of halogen, C1-6 alkyl, -CF3, - OCF3, cyano, C1-6 alkoxy, -NR10R11, -X-aryl, -X-heteroaryl and -X-heterocyclyl; R1, R2, R3, R4 and R5 independently represent hydrogen, fluorine, chlorine, -CF3, cyano or C1-6 alkyl, such that at least one of R1, R2, R3, R4 and R5 is other than hydrogen; R6, R7, R8, R9, R10 and R11 independently represent hydrogen or C1-6 alkyl; X represents a linker selected from a bond, -(CH2)n- and -O-(CH2)n-; and n represents an integer from 1 to 3. The compounds or salts modulate P2X7 receptor function and are capable of antagonizing the effects of ATP at the P2X7 receptor ("P2X7 receptor antagonists").
