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991.
Clapham KM Bardos J Finlay MR Golding BT Griffen EJ Griffin RJ Hardcastle IR Menear KA Ting A Turner P Young GL Cano C 《Bioorganic & medicinal chemistry letters》2011,21(3):966-970
Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110α), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC50 = 8 nM). 相似文献
992.
Kallan NC Spencer KL Blake JF Xu R Heizer J Bencsik JR Mitchell IS Gloor SL Martinson M Risom T Gross SD Morales TH Wu WI Vigers GP Brandhuber BJ Skelton NJ 《Bioorganic & medicinal chemistry letters》2011,21(8):2410-2414
A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA. 相似文献
993.
Sleebs BE Nikolakopoulos G Street IP Falk H Baell JB 《Bioorganic & medicinal chemistry letters》2011,21(19):5992-5994
4-Aminobenzothieno[3,2-d]pyrimidines were previously identified in a high throughput screening campaign as LIMK1 inhibitors. Scaffold reversal led to the identification of a series of simple 5,6-substituted 4-aminothieno[2,3-d]pyrimidines with low micromolar inhibition of LIMK1. 相似文献
994.
995.
Burton MJ Mellor IR Duce IR Davies TG Field LM Williamson MS 《Insect biochemistry and molecular biology》2011,41(9):723-732
Knockdown resistance (kdr) in insects, caused by inherited nucleotide polymorphisms in the voltage-gated sodium channel (VGSC) gene, is a major threat to the efficacy of pyrethroid insecticides. Classic kdr, resulting from an L1014F substitution in the VGSC is now present in numerous pest species. Two other substitutions at the L1014 locus have also been reported, L1014S and L1014H. Here we have used expression of L1014 modified Drosophila para VGSCs in Xenopus oocytes with two-electrode voltage clamp to characterise all three mutations. The mutations L1014F and L1014H caused significant depolarizing shifts in the half activation voltage (V50,act) from −17.3 mV (wild-type) to −13.1 and −13.5 mV respectively, whereas L1014S caused no shift in V50,act but its currents decayed significantly faster than wild-type channels. Treatment of the wild-type channel with deltamethrin (≥1 nM), permethrin (≥30 nM) or DDT (≥1 ??M) resulted in hyperpolarizing shifts in V50,act. Deltamethrin, permethrin and DDT also produced “tail currents” with EC50s of 0.043, 0.40 and 65 ??M and maximum modifications of 837, 325 and 7% respectively. L1014F provided a high level of resistance against all insecticides for both measured parameters. L1014H most effectively combated deltamethrin induced tail currents while L1014S strongly resisted the large DDT induced shifts in V50,act. We conclude that L1014H and L1014S may have arisen through heavy exposure to specific pyrethroids and DDT respectively. 相似文献
996.
Cowley PM Baker J Barn DR Buchanan KI Carlyle I Clark JK Clarkson TR Deehan M Edwards D Goodwin RR Jaap D Kiyoi Y Mort C Palin R Prosser A Walker G Ward N Wishart G Young T 《Bioorganic & medicinal chemistry letters》2011,21(1):497-501
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist. 相似文献
997.
998.
A lead-like kinase inhibitor screening library containing new 3-aminopyrazolopyridinones and closely related compounds was designed that contained hydrogen-bond donor-acceptor motifs and substitution vectors inspired by the natural product kinase inhibitor indirubin. The solubility of the 3-aminopyrazolopyridinone scaffold was more than 1000-fold greater than that of indirubin itself, and solubility was enhanced by reduction of the proportion of lipophilic aryl substituents or the introduction of basic groups. Several components of the library showed kinase inhibitory activity. A subset of diaryl-substituted analogues preferentially inhibited tyrosine kinases with low micromolar activity and good ligand efficiency, and showed cellular antiproliferative activity. The evaluation of the library shows that new, non-natural compounds with relevant biological activity and improved physicochemical properties can be generated from the natural product indirubin, providing compounds that may be useful for kinase inhibitor drug discovery. 相似文献
999.
Maintaining cell volume is critical for cellular function yet shift in cell volume is a prerequisite for mitosis and apoptosis. The ubiquitously and evolutionary conserved serine/threonine kinase CK2 promotes cell survival and suppresses apoptosis. The present review describes how mammalian cells regulate the cellular content of the major cellular organic osmolyte, taurine with emphasis on CK2 mediated regulation of active taurine uptake and volume-sensitive taurine release. Furthermore, we discuss how CK2-mediated regulation of taurine homeostasis is potentially involved in cellular functions such as proliferation and survival. 相似文献
1000.