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71.
Koji Ochiai Satoshi Takita Akihiko Kojima Tomohiko Eiraku Kazuhiko Iwase Tetsuya Kishi Akira Ohinata Yuichi Yageta Tokutaro Yasue David R. Adams Yasushi Kohno 《Bioorganic & medicinal chemistry letters》2013,23(1):375-381
(?)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration. 相似文献
72.
Akihiko Kojima Satoshi Takita Tatsunobu Sumiya Koji Ochiai Kazuhiko Iwase Tetsuya Kishi Akira Ohinata Yuichi Yageta Tokutaro Yasue Yasushi Kohno 《Bioorganic & medicinal chemistry letters》2013,23(19):5311-5316
We previously identified KCA-1490 [(?)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model. 相似文献
73.
Takahiro Kawabe Warrick Roseboom Shin'ya Nishida 《Proceedings. Biological sciences / The Royal Society》2013,280(1763)
Sense of agency, the experience of controlling external events through one''s actions, stems from contiguity between action- and effect-related signals. Here we show that human observers link their action- and effect-related signals using a computational principle common to cross-modal sensory grouping. We first report that the detection of a delay between tactile and visual stimuli is enhanced when both stimuli are synchronized with separate auditory stimuli (experiment 1). This occurs because the synchronized auditory stimuli hinder the potential grouping between tactile and visual stimuli. We subsequently demonstrate an analogous effect on observers'' key press as an action and a sensory event. This change is associated with a modulation in sense of agency; namely, sense of agency, as evaluated by apparent compressions of action–effect intervals (intentional binding) or subjective causality ratings, is impaired when both participant''s action and its putative visual effect events are synchronized with auditory tones (experiments 2 and 3). Moreover, a similar role of action–effect grouping in determining sense of agency is demonstrated when the additional signal is presented in the modality identical to an effect event (experiment 4). These results are consistent with the view that sense of agency is the result of general processes of causal perception and that cross-modal grouping plays a central role in these processes. 相似文献
74.
Yuji Nakamura Teppei Fujimoto Yasuyuki Ogawa Hidenori Namiki Sayaka Suzuki Masayoshi Asano Chie Sugita Akiyoshi Mochizuki Shojiro Miyazaki Kazuhiko Tamaki Yoko Nagai Shin-ichi Inoue Takahiro Nagayama Mikio Kato Katsuyoshi Chiba Kiyoshi Takasuna Takahide Nishi 《Bioorganic & medicinal chemistry》2013,21(11):3175-3196
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure–activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h. 相似文献
75.
76.
Kenji Seiwa Yoshiko Miwa Shigetoshi Akasaka Hiroshi Kanno Mizuki Tomita Tomoyuki Saitoh Naoto Ueno Megumi Kimura Yoichi Hasegawa Miki Konno Kazuhiko Masaka 《Ecological Research》2013,28(1):29-41
To evaluate the extent to which landslides affect community dynamics and consequent species diversity in a beech-dominated forest, differences in the composition and size structure of tree species were compared between landslide and adjacent stable (control) stands. Demography and changes in size were compared between the two stands over a 5-year period about 60 years after a landslide. In the control stand, replacement occurred even amongst late-successional species, with beech (Fagus crenata)—the most dominant species—increasing in relative abundance. In the landslide stand, very few large individuals of late-successional species occurred, whereas large individuals of early-successional species occurred only in the landslide stand. The traits indicate that the landslide strongly facilitated species diversity, not only by reducing the dominance of late-successional species, but also by promoting recruitment of early-successional species. However, new recruitment of early-successional species was inhibited in the landslide stand, although we observed succeeding regeneration and subsequent population growth of late-successional species there. As a result, the relative dominance of late-successional species increased with succession after the landslide, thus decreasing future species diversity. In beech-dominant forest landscapes in Japan that include communities with different developmental stages, the mosaic of serial stages may facilitate species diversity after a landslide. 相似文献
77.
78.
79.
The reversible interaction between dextran sulfate (D) and the low density lipoprotein of human serum (P) was investigated by sedimentation velocity. Analysis of the velocity patterns of dextran sulfate—lipoprotein mixtures revealed that the maximum number of binding sites on dextran sulfate molecule is approximately 6. It was also shown that the species of the complex formed is affected by the mixing ratio of the two constituents: at the molar ratio (P/D) 0.69, the complex exists in average as DP1.6 and at 0.98 as DP2.2. The linear increment of sedimentation coefficient of the complex due to the binding of one lipoprotein molecule was 7.8S. Finally, the mechanism of precipitation of the complexes was discussed. 相似文献
80.
Shuichi Kaminogawa Shun-ichi Dosako Kunio Yamauchi Kazuhiko Kinoshita 《Bioscience, biotechnology, and biochemistry》2013,77(2):533-539
Conjugates of αs1-,κ-caseins and αs1-,κ-casein complex were prepared with dimethylaminonaphthalenesulfonate and pyrenebutyrate. Their fluorescence lifetimes and the rotational relaxation times were measured by single photon counting technique and fluorescence depolarization technique, respectively. Both dimethylaminonaphthalenesulfonate and pyrenebutyrate conjugates had more than two lifetimes and the longer lifetime of pyrenebutyrate conjugates was near 140 nsec.The rotational relaxation time of pyrenebutyrate αs1-,κ-casein complex was smaller than that of pyrenebutyrate κ-casein polymer, which suggested that the complex formation of αs1- and κ-casein polymers led to dissociation of the κ-casein polymer.Changes of the rotational relaxation time as a function of weight ratio of αs1- and κ-casein polymers (αs1/κ) showed the specific variation and it was suggested that 4 moles of αs1-κ-casein complex were formed from one mole of κ-casein polymer. 相似文献