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11.
Li Q Li T Zhu GD Gong J Claibone A Dalton C Luo Y Johnson EF Shi Y Liu X Klinghofer V Bauch JL Marsh KC Bouska JJ Arries S De Jong R Oltersdorf T Stoll VS Jakob CG Rosenberg SH Giranda VL 《Bioorganic & medicinal chemistry letters》2006,16(6):1679-1685
A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC(50) values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined. 相似文献
12.
Zheng GZ Bhatia P Kolasa T Patel M El Kouhen OF Chang R Uchic ME Miller L Baker S Lehto SG Honore P Wetter JM Marsh KC Moreland RB Brioni JD Stewart AO 《Bioorganic & medicinal chemistry letters》2006,16(18):4936-4940
We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models. 相似文献
13.
Faghih R Dwight W Pan JB Fox GB Krueger KM Esbenshade TA McVey JM Marsh K Bennani YL Hancock AA 《Bioorganic & medicinal chemistry letters》2003,13(7):1325-1328
Novel 4'-[(NR1R2-1-yl)]-propoxy-biaryl-4-carboxamides were designed and synthesized. All compounds were tested for affinity at histamine H(3)receptors. Most compounds were highly potent and selective for human and rat H(3) receptors and selected examples such as A-349821 showed functional antagonism of H(3) receptors in vitro and in a mouse dipsogenia model. 相似文献
14.
15.
LM Harris L Blank RP Desai NE Welker ET Papoutsakis 《Journal of industrial microbiology & biotechnology》2001,27(5):322-328
The effect of solR inactivation on the metabolism of Clostridium acetobutylicum was examined using fermentation characterization and metabolic flux analysis. The solR-inactivated strain (SolRH) of this study had a higher rate of glucose utilization and produced higher solvent concentrations
(by 25%, 14%, and 81%, respectively, for butanol, acetone, and ethanol) compared to the wild type. Strain SolRH(pTAAD), carrying
a plasmid-encoded copy of the bifunctional alcohol/aldehyde dehydrogenase gene (aad) used in butanol production, produced even higher concentrations of solvents (by 21%, 45%, and 62%, respectively, for butanol,
acetone, and ethanol) than strain SolRH. Clarithromycin used for strain SolRH maintenance during SolRH(pTAAD) fermentations
did not alter product formation; however, tetracycline used for pTAAD maintenance resulted in 90% lower solvent production.
Journal of Industrial Microbiology & Biotechnology (2001) 27, 322–328.
Received 12 September 2000/ Accepted in revised form 21 July 2001 相似文献
16.
Doherty GA Bhatia P Vortherms TA Marsh KC Wetter JM Mack H Scott VE Jarvis MF Stewart AO 《Bioorganic & medicinal chemistry letters》2012,22(4):1716-1718
A novel series of diphenyl lactam containing calcium channel blockers is described. Extensive SAR studies resulted in compounds with low molar activity and good plasma exposure after oral dosing. Compounds 2, 6 and 7 demonstrated significant efficacy in the capsaicin model of secondary hyperalgesia following oral administration. 相似文献
17.
Thomas SA Li T Woods KW Song X Packard G Fischer JP Diebold RB Liu X Shi Y Klinghofer V Johnson EF Bouska JJ Olson A Guan R Magnone SR Marsh K Luo Y Rosenberg SH Giranda VL Li Q 《Bioorganic & medicinal chemistry letters》2006,16(14):3740-3744
Based on lead compounds 2 and 3 a series of 3,5-disubstituted pyridines have been designed and evaluated for inhibition of AKT/PKB. Modifications at the 3 position of the pyridine ring led to a number of potent compounds with improved physical properties, resulting in the identification of 11g as a promising, orally active Akt inhibitor. The synthesis, structure-activity relationship studies, and pharmacokinetic data are presented in this paper. 相似文献
18.
The objectives of this study were to estimate the incidence and describe the pattern and severity of training injuries in taekwondo, and to compare pattern and severity of training injuries with competition injuries. One hundred and fifty-two active Australian amateur taekwondo athletes, aged 12 years or over, completed an online survey comprising questions on training exposure and injury history over the preceding 12 months. The main outcome measures were: overall injury incidence rate per athlete-year; training injury incidence rate per athlete-year, per 1000 athlete-training-sessions, and per 1000 athlete-hours of training; injury severity; and injury proportions by anatomical region and by type of injury. Injury incidence rates were calculated with 95% confidence intervals using standard methods, while injury proportions were compared using Fisher''s exact test. The vast majority (81.5%) of taekwondo injuries in an average athlete-year occurred during training. The training injury incidence rate was estimated to be 1.6 (95% CI: 1.4, 1.9) per athlete-year, 11.8 (95% CI: 10.4, 13.4) per 1000 athlete-training-sessions, and 7.0 (95% CI: 6.1, 7.9) per 1000 athlete-hours of training. Among athletes with five or fewer injuries, the severity and injury pattern of training injuries were, by and large, the same as for competition injuries. Approximately sixty percent (60.3%) of training injuries required treatment by a health professional. Considering the burden of training injuries exceeds that of competition injuries, taekwondo governing bodies and stakeholders are encouraged to devote more efforts towards the identification of risk factors for, and prevention of, training injuries in the sport of taekwondo. 相似文献
19.
Wang L Lin NH Li Q Henry RF Zhang H Cohen J Gu WZ Marsh KC Bauch JL Rosenberg SH Sham HL 《Bioorganic & medicinal chemistry letters》2004,14(18):4603-4606
Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbonitrile was established. The structure of compound 5c was confirmed by X-ray crystallography. 相似文献
20.
Drizin I Gomtsyan A Bayburt EK Schmidt RG Zheng GZ Perner RJ DiDomenico S Koenig JR Turner SC Jinkerson TK Brown BS Keddy RG McDonald HA Honore P Wismer CT Marsh KC Wetter JM Polakowski JS Segreti JA Jarvis MF Faltynek CR Lee CH 《Bioorganic & medicinal chemistry》2006,14(14):4740-4749
Novel 5,6-fused heteroaromatic ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that 4-aminoindoles and indazoles are the preferential cores for the attachment of ureas. Bulky electron-withdrawing groups in the para-position of the aromatic ring of the urea substituents imparted the best in vitro potency at TRPV1. The most potent derivatives were assessed in in vivo inflammatory and neuropathic pain models. Compound 46, containing the indazole core and a 3,4-dichlorophenyl group appended to it via a urea linker, demonstrated in vivo analgesic activity upon oral administration. This derivative also showed selectivity versus other receptors in the CEREP screen and exhibited acceptable cardiovascular safety at levels exceeding the therapeutic dose. 相似文献