排序方式: 共有74条查询结果,搜索用时 31 毫秒
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Mathivanan Packiarajan Michel Grenon Samuel Zorn Allen T. Hopper Andrew D. White Gamini Chandrasena Xiaosui Pu Robbin M. Brodbeck Albert J. Robichaud 《Bioorganic & medicinal chemistry letters》2013,23(14):4037-4043
A new series of potent fused thiazole mGlu5 receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu5 PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu5 negative allosteric modulators (NAMs). 相似文献
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Ahmad S Ngu K Combs DW Wu SC Weinstein DS Liu W Chen BC Chandrasena G Dorso CR Kirby M Atwal KS 《Bioorganic & medicinal chemistry letters》2004,14(1):177-180
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability. 相似文献
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1. The increase of species richness with the area of the habitat sampled, that is the species–area relationship, and its temporal analogue, the species–time relationship (STR), are among the few general laws in ecology with strong conservation implications. However, these two scale‐dependent phenomena have rarely been considered together in biodiversity assessment, especially in freshwater systems. 2. We examined how the spatial scale of sampling influences STRs for a Central‐European stream fish assemblage (second‐order Bernecei stream, Hungary) using field survey data in two simulation‐based experiments. 3. In experiment one, we examined how increasing the number of channel units, such as riffles and pools (13 altogether), and the number of field surveys involved in the analyses (12 sampling occasions during 3 years), influence species richness. Complete nested curves were constructed to quantify how many species one observes in the community on average for a given number of sampling occasions at a given spatial scale. 4. In experiment two, we examined STRs for the Bernecei fish assemblage from a landscape perspective. Here, we evaluated a 10‐year reach level data set (2000–09) for the Bernecei stream and its recipient watercourse (third‐order Kemence stream) to complement results on experiment one and to explore the mechanisms behind the observed patterns in more detail. 5. Experiment one indicated the strong influence of the spatial scale of sampling on the accumulation of species richness, although time clearly had an additional effect. The simulation methodology advocated here helped to estimate the number of species in a diverse combination of spatial and temporal scale and, therefore, to determine how different scale combinations influence sampling sufficiency. 6. Experiment two revealed differences in STRs between the upstream (Bernecei) and downstream (Kemence) sites, with steeper curves for the downstream site. Equations of STR curves were within the range observed in other studies, predominantly from terrestrial systems. Assemblage composition data suggested that extinction–colonisation dynamics of rare, non‐resident (i.e. satellite) species influenced patterns in STRs. 7. Our results highlight that the determination of species richness can benefit from the joint consideration of spatial and temporal scales in biodiversity inventory surveys. Additionally, we reveal how our randomisation‐based methodology may help to quantify the scale dependency of diversity components (α, β, γ) in both space and time, which have critical importance in the applied context. 相似文献
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Packiarajan M Marzabadi MR Desai M Lu Y Noble SA Wong WC Jubian V Chandrasena G Wolinsky TD Zhong H Walker MW Wiborg O Andersen K 《Bioorganic & medicinal chemistry letters》2011,21(18):5436-5441
The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress. 相似文献
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Kastrati I Edirisinghe PD Hemachandra LP Chandrasena ER Choi J Wang YT Bolton JL Thatcher GR 《PloS one》2011,6(11):e27876
There is association between exposure to estrogens and the development and progression of hormone-dependent gynecological cancers. Chemical carcinogenesis by catechol estrogens derived from oxidative metabolism is thought to contribute to breast cancer, yet exact mechanisms remain elusive. Malignant transformation was studied in MCF-10A human mammary epithelial cells, since estrogens are not proliferative in this cell line. The human and equine estrogen components of estrogen replacement therapy (ERT) and their catechol metabolites were studied, along with the influence of co-administration of selective estrogen receptor modulators (SERMs), raloxifene and desmethyl-arzoxifene (DMA), and histone deacetylase inhibitors. Transformation was induced by human estrogens, and selectively by the 4-OH catechol metabolite, and to a lesser extent by an equine estrogen metabolite. The observed estrogen-induced upregulation of CYP450 1B1 in estrogen receptor negative MCF-10A cells, was compatible with a causal role for 4-OH catechol estrogens, as was attenuated transformation by CYP450 inhibitors. Estrogen-induced malignant transformation was blocked by SERMs correlating with a reduction in formation of nucleobase catechol estrogen (NCE) adducts and formation of 8-oxo-dG. NCE adducts can be formed consequent to DNA abasic site formation, but NCE adducts were also observed on incubation of estrogen quinones with free nucleotides. These results suggest that NCE adducts may be a biomarker for cellular electrophilic stress, which together with 8-oxo-dG as a biomarker of oxidative stress correlate with malignant transformation induced by estrogen oxidative metabolites. The observed attenuation of transformation by SERMs correlated with these biomarkers and may also be of clinical significance in breast cancer chemoprevention. 相似文献
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Hye-Yeong Kim Johann Sohn Gihani T. Wijewickrama Praneeth Edirisinghe Teshome Gherezghiher Madhubani Hemachandra Pei-Yi Lu R. Esala Chandrasena Mary Ellen Molloy Debra A. Tonetti Gregory R.J. Thatcher 《Bioorganic & medicinal chemistry》2010,18(2):809-821
Cyclodextrin (CD) is a well known drug carrier and excipient for enhancing aqueous solubility. CDs themselves are anticipated to have low membrane permeability because of relatively high hydrophilicity and molecular weight. CD derivatization with 17-beta estradiol (E2) was explored extensively using a number of different click chemistries and the cell membrane permeability of synthetic CD–E2 conjugate was explored by cell reporter assays and confocal fluorescence microscopy. In simile with reported dendrimer–E2 conjugates, CD–E2 was found to be a stable, extranuclear receptor selective estrogen that penetrated into the cytoplasm. 相似文献
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Michael D Kennedy Mark J Haykowsky Carol A Boliek Ben TA Esch Jessica M Scott Darren ER Warburton 《Dynamic medicine : DM》2006,5(1):8