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41.
Duan M Kazmierski WM Chong PY Deanda F Edelstein M Ferris R Peckham J Wheelan P Xiong Z Zhang H Nishizawa R Takaoka Y 《Bioorganic & medicinal chemistry letters》2011,21(21):6470-6475
A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles. 相似文献
42.
Nishizawa R Nishiyama T Hisaichi K Minamoto C Murota M Takaoka Y Nakai H Tada H Sagawa K Shibayama S Fukushima D Maeda K Mitsuya H 《Bioorganic & medicinal chemistry》2011,19(13):4028-4042
Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented. 相似文献
43.
Christakis and colleagues have shown that health behaviors cluster in social networks and suggest social norms may account for the clustering. This study examined: (i) whether obesity clusters among young adults and whether social norms do in fact account for the clustering, and (ii) among overweight/obese (OW/OB) young adults, whether number of social contacts trying to lose weight is associated with weight loss intentions and whether social norms for weight loss account for this effect. Normal weight (NW) and OW/OB young adults (N = 288; 66% female; 75% white) completed measures assessing number of OW social contacts and social norms for obesity. OW/OB young adults also indicated number of OW social contacts currently trying to lose weight, social norms for weight loss, and weight loss intentions. Compared to NW, OW/OB young adults were more likely to have OW romantic partners and best friends and had more OW casual friends and family members (Ps < 0.05), but social norms for obesity did not differ between groups, and social norms did not mediate the relationship between OW social contacts and participants' weight status. However, among OW/OB young adults, having more social contacts trying to lose weight was associated with greater intention to lose weight (r = 0.20, P = 0.02) and social norms for weight loss fully mediated this effect (P < 0.01). This study is the first to show that social contacts and normative beliefs influence weight status and intentions for weight control in young adults. Findings underscore the importance of targeting social influence in the treatment and prevention of obesity in this high-risk age group. 相似文献
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The model plant pathogen Pseudomonas syringae pv. tomato DC3000 grows and produces necrotic lesions in the leaves of its host, tomato. Both abilities are dependent upon the hypersensitive response and pathogenicity (Hrp) type III secretion system (TTSS), which translocates multiple effector proteins into plant cells. A previously constructed DC3000 mutant with a 9.3-kb deletion in the Hrp pathogenicity island conserved effector locus (CEL) was strongly reduced in growth and lesion formation in tomato leaves. The ACEL mutation affects three putative or known effector genes: avrE1, hopM1, and hopAA1-1. Comparison of genomic sequences of DC3000, P. syringae pv. phaseolicola 1448A, and P. syringae pv. syringae B728a revealed that these are the only effector genes present in the CEL of all three strains. AvrEl was shown to carry functional TTSS translocation signals based on the performance of a fusion of the first 315 amino acids of AvrE1 to the Cya translocation reporter. A DC3000 delta avrE1 mutant was reduced in its ability to produce lesions but not in its ability to grow in host tomato leaves. AvrE1 expressed from the 35S promoter elicited cell death in nonhost Nicotiana tabacum leaves and host tomato leaves in Agrobacterium-mediated transient expression experiments. Mutations involving combinations of avrE1, hopM1, and hopAA1-1 revealed that deletion of both avrE1 and hopM1 reproduced the strongly reduced growth and lesion phenotype of the delta CEL mutant. Furthermore, quantitative assays involving different levels of inoculum and electrolyte leakage revealed that the avrE1/hopM1 and deltaCEL mutants both were partially impaired in their ability to elicit the hypersensitive response in nonhost N. benthamiana leaves. However, the avrE1/hopM1 mutant was not impaired in its ability to deliver AvrPto1(1-100)-Cya to nonhost N. benthamiana or host tomato leaves during the first 9 h after inoculation. These data suggest that AvrE1 acts within plant cells and promotes lesion formation and that the combined action of AvrE1 and HopM1 is particularly important in promoting bacterial growth in planta. 相似文献
46.
Simeone JP Bugianesi RL Ponpipom MM Yang YT Lo JL Yudkovitz JB Cui J Mount GR Ren RN Creighton M Mao AH Vincent SH Cheng K Goulet MT 《Bioorganic & medicinal chemistry letters》2002,12(22):3329-3332
The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs. 相似文献
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Rena A. Mizrahi Kelly J. Phelps Andrea Y. Ching Peter A. Beal 《Nucleic acids research》2012,40(19):9825-9835
Adenosine deaminases acting on RNA (ADAR1 and ADAR2) are human RNA-editing adenosine deaminases responsible for the conversion of adenosine to inosine at specific locations in cellular RNAs. Since inosine is recognized during translation as guanosine, this often results in the expression of protein sequences different from those encoded in the genome. While our knowledge of the ADAR2 structure and catalytic mechanism has grown over the years, our knowledge of ADAR1 has lagged. This is due, at least in part, to the lack of well defined, small RNA substrates useful for mechanistic studies of ADAR1. Here, we describe an ADAR1 substrate RNA that can be prepared by a combination of chemical synthesis and enzymatic ligation. Incorporation of adenosine analogs into this RNA and analysis of the rate of ADAR1 catalyzed deamination revealed similarities and differences in the way the ADARs recognize the edited nucleotide. Importantly, ADAR1 is more dependent than ADAR2 on the presence of N7 in the edited base. This difference between ADAR1 and ADAR2 appears to be dependent on the identity of a single amino acid residue near the active site. Thus, this work provides an important starting point in defining mechanistic differences between two functionally distinct human RNA editing ADARs. 相似文献
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