72436-33-0Relevant articles and documents
Carbazole compound as Autotaxin inhibitor, preparation method therefor and application of carbazole compound
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, (2018/01/04)
The invention belongs to the technical field of biological pharmaceuticals and aims at providing a carbazole compound as an Autotaxin inhibitor, use of the compound in preparation of drugs for targeted inhibition of activity of the Autotaxin, use of the compound in preparation of drugs for treating and preventing diseases or symptoms caused by rising of lysophosphatidic acid and the Autotaxin, and use of the compound in preparation of antitumor drugs. The compound is a 2,7-substituted carbazole derivative, particularly 5-[7-(4-R2-benzyloxy)-9H-carbazol-2-methylene]-2-R1 phenol, R1-SWS-R2 for short, wherein R1 is methyl or ethyl, and R2 is any one of halogen, boric acid, sulfonyl, phospho, carboxyl and amino acid. The compound has very good anti-tumor activity to autocrine high-expression cell lines and has un-obvious influence on low-expression cell lines. The compound can be used for preparing corresponding antitumor drugs and provides possibility for designing novel Autotaxin inhibitors.
Structure-activity relationship studies on N3-substituted willardiine derivatives acting as AMPA or kainate receptor antagonists
Dolman, Nigel P.,More, Julia C. A.,Alt, Andrew,Knauss, Jody L.,Troop, Helen M.,Bleakman, David,Collingridge, Graham L.,Jane, David E.
, p. 2579 - 2592 (2007/10/03)
N3-Substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and kainate receptor antagonists. In an attempt to improve the potency and selectivity of these AMPA and kainate receptor antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (5′)-1-(2-Amino-2-carboxyethyl)-3-(2- carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLUK5-containing kainate receptors (KD 0.105 ± 0.007 μM vs kainate on native GLUK5; KD 71.4 ± 8.3 μM vs (S)-5- fluorowillardiine on native AMPA receptors). On recombinant human GLU K5, GLUK5/GLUK6, and GLUK5/GLU K2, KB values of 0.12 ± 0.03, 0.12 ± 0.01, and 0.18 ± 0.02 μM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLUK6 or GLUK7 kainate receptors or homomeric GLUA1-4 AMPA receptors (IC50 values > 100 μM). Thus, 43 is a potent and selective GLUK5 receptor antagonist.
Structure-Activity Relationships of Small Phosphopeptides, Inhibitors of Grb2 SH2 Domain, and Their Prodrugs
Liu, Wang-Qing,Vidal, Michel,Olszowy, Catherine,Million, Emmanuelle,Lenoir, Christine,Dh?tel, Hélène,Garbay, Christiane
, p. 1223 - 1233 (2007/10/03)
To develop potential antitumor agents directed toward HER2/ErbB2 overexpression in cancer, we have designed inhibitors of the recognition between the phosphotyrosine of the receptor and the SH2 domain of the adaptor protein Grb2. In the first part of the paper, we report the synthesis of mimetics of the constrained (α-Me)phosphotyrosine residue such as (α-Me)-4-phosphonomethylphenylalanine (-CH2PO3H 2), (α-Me) 4-phosphonodifluoromethylphenylalanine (-CF 2PO3H2), and (α -Me)-4-phosphonophenylalanine (-PO3H2). The incorporation of these residues in the mAZ-pTyr-Xaa-Asn-NH2 series provided compounds with very high affinity for the Grb2 SH2 domain, in the 10 -8-10-9 range of Kd values. These compounds behave as potent antagonists of the Grb2-Shc interaction. Our results highlight the importance of the doubly negative charge borne by the pY + 1 amino acid in accordance with the interactions observed in the complex crystallized between mAZ-pTyr-(αMe)pTyr-Asn-NH2 and the Grb2 SH2 domain. mAZ-pTyr-(αMe)pTyr-Asn-NH2 was derivatized as the S-acetyl thioester (SATE) of the phosphotyrosine residues, and its surrogates provided prodrugs with very potent antiproliferative activity on cells overexpressing HER2/ErbB2, with ED50 values amounting to 0.1 μM. Finally a new prodrug is put forth under the form of a monobenzyl ester of phosphate group that is as active as and much easier to synthesize than SATE prodrugs. These compounds show promising activity for further testing on in vivo models.
