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排序方式: 共有1940条查询结果,搜索用时 52 毫秒
61.
Thomas Troxler Paulette Greenidge Kaspar Zimmermann Sandrine Desrayaud Peter Drückes Tatjana Schweizer Daniela Stauffer Giorgio Rovelli Derya R. Shimshek 《Bioorganic & medicinal chemistry letters》2013,23(14):4085-4090
Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase activity of LRRK2 in PD. Several LRRK2 inhibitors have been reported to date. Here, we report a selective, brain penetrant LRRK2 inhibitor and demonstrate by a competition pulldown assay in vivo target engagement in mice. 相似文献
62.
Shuji Yonezawa Hidekuni Yamakawa Chie Muto Motoko Hosono Takahiko Yamamoto Kazunari Hattori Masahiro Sakagami Hiroko Togame Yoshikazu Tanaka Toru Nakano Hiroshi Takemoto Mitsuhiro Arisawa Satoshi Shuto 《Bioorganic & medicinal chemistry letters》2013,23(10):2912-2915
To improve the efficacy of the conformationally restricted BACE1 inhibitors, structural modifications were investigated using two strategies: (a) modification of the terminal aromatic ring and (b) insertion of a spacer between the aromatic rings. In the latter approach, another type of inhibitor 17 bearing an ethylene spacer between two aromatic rings was found to exhibit good BACE1 inhibitory activity, while the corresponding conformationally unrestricted compound 25 showed no activity. This result revealed an interesting effect of a conformational restriction with a cyclopropane ring. 相似文献
63.
Seong Rim Byeon Hyunjin Vincent Kim Mijin Jeon Young Gil Ahn Maeng Sup Kim Jae Yang Kong Hye Yun Kim Young Soo Kim Dong Jin Kim 《Bioorganic & medicinal chemistry letters》2013,23(11):3467-3469
Alzheimer’s disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F = 46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013. 相似文献
64.
Hye Ri Park Jiyoon Kim Taekeun Kim Seonmi Jo Miyoung Yeom Bongjin Moon Il Han Choo Jaeick Lee Eun Jeong Lim Ki Duk Park Sun-Joon Min Ghilsoo Nam Gyochang Keum C. Justin Lee Hyunah Choo 《Bioorganic & medicinal chemistry》2013,21(17):5480-5487
In Parkinson’s disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson’s disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson’s disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure–activity relationship study revealed that the piperidino group was the best choice for the R1 amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5 nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5 nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives. 相似文献
65.
Hualong Fu Lihai Yu Mengchao Cui Jinming Zhang Xiaojun Zhang Zijing Li Xuedan Wang Jianhua Jia Yanping Yang Pingrong Yu Hongmei Jia Boli Liu 《Bioorganic & medicinal chemistry》2013,21(13):3708-3714
A novel series of fluorinated 2-phenylindole derivatives were synthesized and evaluated as β-amyloid imaging probes for PET. The in vitro inhibition assay demonstrated that their binding affinities for Aβ1–42 aggregates ranged from 28.4 to 1097.8 nM. One ligand was labeled with 18F ([18F]1a) for its high affinity (Ki = 28.4 nM), which was also confirmed by in vitro autoradiography experiments on brain sections of transgenic mouse (C57BL6, APPswe/PSEN1, 11 months old, male). In vivo biodistribution experiments in normal mice showed that this radiotracer displayed high initial uptake (5.82 ± 0.51% ID/g at 2 min) into and moderate washout (2.77 ± 0.31% ID/g at 60 min) from the brain. [18F]1a could be developed as a promising new PET imaging probe for Aβ plaques although necessary modifications are still needed. 相似文献
66.
《Bioorganic & medicinal chemistry》2013,21(23):7406-7417
A series of Tacrine–Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood–brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer’s disease (AD). 相似文献
67.
Phuong-Thao Tran Van-Hai Hoang Shivaji A. Thorat Sung Eun Kim Jihyae Ann Yu Jin Chang Dong Woo Nam Hyundong Song Inhee Mook-Jung Jiyoun Lee Jeewoo Lee 《Bioorganic & medicinal chemistry》2013,21(13):3821-3830
In an effort to design inhibitors of human glutaminyl cyclase (QC), we have synthesized a library of N-aryl N-(5-methyl-1H-imidazol-1-yl)propyl thioureas and investigated the contribution of the aryl region of these compounds to their structure–activity relationships as cyclase inhibitors. Our design was guided by the proposed binding mode of the preferred substrate for the cyclase. In this series, compound 52 was identified as the most potent QC inhibitor with an IC50 value of 58 nM, which was two-fold more potent than the previously reported lead 2. Compound 52 is a most promising candidate for future evaluation to monitor its ability to reduce the formation of pGlu-Aβ and Aβ plaques in cells and transgenic animals. 相似文献
68.
《Bioscience, biotechnology, and biochemistry》2013,77(5):750-752
A process was developed to produce a characteristic milk gel. Raw and market milk samples were freeze-concentrated using bacterial ice nuclei. The concentrates were kept at 5°C and compressed at 300–600 MPa for 5 min. The combination of the freeze concentration and the pressurization gave a milk gel without adding any gelling agents. The addition of sugar at 10% to the concentrated milk improved its gel strength and viscoelasticity. The gel was characterized by a phase transition at about 62–75°C. 相似文献
69.
《Bioscience, biotechnology, and biochemistry》2013,77(8):1496-1501
Since the soluble oligomers of 42-residue amyloid β (Aβ42) might be neurotoxins at an early stage of Alzheimer’s disease (AD), inhibition of soluble Aβ42 oligomerization should be effective in the treatment of AD. We have found by phage display that a 7-residue peptide, SRPGLRR, exhibited inhibitory activity against soluble 37/48 kDa oligomers of Aβ42. In the present study, we newly prepared 3- and 4-residue random peptides libraries and performed pannings of them against soluble Aβ42 to search for important factors in the inhibition of Aβ42 oligomerization. After the fifth round, arginine-containing peptides were enriched in both libraries. SDS–PAGE and size-exclusion chromatography indicated that the inhibitory activities of 4-residue peptides against the soluble 37/48 kDa oligomers of Aβ42 were higher than those of the 3-residue peptides, and RFRK exhibited strong inhibitory activity as well as SRPGLRR. These short peptides should be useful for the suppression of soluble Aβ42 oligomer formation. 相似文献
70.
P. Gurusaravanan S. Vinoth M. Satheesh Kumar N. Thajuddin N. Jayabalan 《Journal of Genetic Engineering and Biotechnology》2013,11(1):9-16
The challenging task of bringing high efficiency transformed plants attracts lot of attention in recent times. In search for this, there have been many attempts made using, different techniques like tissue culture and plant breeding methods. Here we report a suitable alternative facile route, where cyanobacterial extracellular products are utilized as growth regulators and its performance validated on Gossypium hirsutum L. MS medium is tested with cyanobacterial extracellular products of Nostoc ellipsosporum, Dolichospermum flos-aquae and Oscillatoria acuminata .Our best results show that the addition of O. acuminata extracellular product with plant growth hormones gives the excellent induction and elongation in cotton. In addition to this, the multiple shoot was obtained on MS medium fortified with 1.0 mg L?1 BA with 8% O. acuminata and 1.5 mg L?1 TDZ with 12% O. acuminata. High frequency of shoot elongation supplemented with MS medium, iP 2.5 mg L?1 and 16% O. acuminata and root production MS medium fortified with 12% O. acuminata best responsible for regeneration in cotton plants. The rooted plants were hardened and transferred to soil with 90% survival rate. 相似文献