- Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors
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Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of the phenyl ring, and made a variety of N-aryl-N′-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC50 = 1.7 μM) and enhanced doxorubicin cytotoxicity (IC50 = 0.44 μM) while displaying no single agent activity.
- Li, Gaoquan,Hasvold, Lisa A.,Tao, Zhi-Fu,Wang, Gary T.,Gwaltney II, Stephen L.,Patel, Jyoti,Kovar, Peter,Credo, Robert B.,Chen, Zehan,Zhang, Haiying,Park, Chang,Sham, Hing L.,Sowin, Thomas,Rosenberg, Saul H.,Lin, Nan-Horng
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p. 2293 - 2298
(2007/10/03)
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- Arylcarbamate derivatives of 1-piperidineethanol as potent ligands for 5-HT4 receptors
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A series of carbamate derivatives (7) of 2-(1-piperidinyl)ethyl 4- amino-5-chloro-2-methoxybenzoates, which have been described as potent agonists and antagonists of 5-HT4 receptors, were synthesized. They were evaluated using radioligand binding assays with [3H]GR 113808, a 5-HT4 receptor selective ligand, in the rat striatum and the electrically stimulated myenteric plexus longitudinal muscle of the guinea pig. In contrast to the previously described ester derivatives, a drop in the affinity for 5-HT4 receptors was observed and the compounds were inactive as agonists in the guinea pig ileum preparation. Unexpectedly, the ortho- substituted carbamates 8b,c (R' = H, RO = MeO or EtO, R'' = H) had nanomolar affinity for 5-HT4 receptors (K(i) = 8.9 ± 0.5 and 2.6 ± 0.4 nM, respectively). As reported previously, the cis- or trans-3,5-dimethyl substitution of piperidine (8n,o) was particularly favorable (K(i) = 1.1 ± 0.6 nM for both isomers). 8c is an antagonist equipotent to the 5-HT4 receptor antagonist SDZ 205-557 (1).
- Soulier, Jean-Louis,Yang, Donglai,Brémont, Béatrice,Croci, Tiziano,Guzzi, Umberto,Langlois, Michel
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p. 1755 - 1761
(2007/10/03)
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- N-Substituted 2-methoxybenzenesulphonamides and medicaments containing them
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The invention relates to new N-substituted benzenesulphonamides of general formula STR1 in which N IS 2 OR 3, R1 and R2 are hydrogen atoms, methyl, ethyl groups, or jointly form with the nitrogen a nitrogenized heterocyclic ring having 5 or 6 members, in particular a piperidino, pyrrolidino or morpholino group, R3 is a hydrogen atom, an NO2 group, an NH2 group, or a halogen, R4 is a hydrogen, a halogen, an NH2 group or a sulphonamide group. These compounds are useful as active substances of medicaments, in particular as antiemetic.
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- Unsymmetrical 1:2-chromium complexes containing an azo compound and an azomethine compound
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Compounds of the formula: STR1 WHICH ARE EMINENTLY SUITABLE FOR DYEING NATURAL AND SYNTHETIC POLYAMIDES AND FOR COLORING SURFACE COATINGS. Dyeings on textile material are distinguished by very good lightfastness and very good fastness to wet treatments, for example fastness to water, perspiration, sea water and washing.
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