共查询到20条相似文献,搜索用时 15 毫秒
1.
Kwan-Young Jung Joong-Heui Cho Jung Sun Lee Hyo Jun Kim Yong-Chul Kim 《Bioorganic & medicinal chemistry》2013,21(9):2643-2650
Carboxylic acid derivatives of pyridoxal were developed as potent P2X1 and P2X3 receptor antagonists with modifications of a lead compound, pyridoxal-5′-phosphate-6-azophenyl-2′,5′-disulfonate (5b, iso-PPADS). The designing strategies included the modifications of aldehyde, phosphate or sulfonate groups of 5b, which may be interacted with lysine residues of the receptor binding pocket, to weak anionic carboxylic acid groups. The corresponding carboxylic acid analogs of pyridoxal-5′-phosphate (1), 13 and 14, showed parallel antagonistic potencies. Also, most of 6-azophenyl derivatives (24–28) of compound 13 or 14 showed potent antagonistic activities similar to that of 5b at human P2X3 receptors with 100 nM range of IC50 values in two-electrode voltage clamp (TEVC) assay system on the Xenopus oocyte. The results indicated that aldehyde and phosphoric or sulfonic acids in 5b could be changed to a carboxylic acid without affecting antagonistic potency at mouse P2X1 and human P2X3 receptors. 相似文献
2.
Toshitake Kobayashi Satoshi Sasaki Naoki Tomita Seiji Fukui Noritaka Kuroda Masaharu Nakayama Atsushi Kiba Yoshihiro Takatsu Tetsuya Ohtaki Fumio Itoh Atsuo Baba 《Bioorganic & medicinal chemistry》2010,18(11):3841-3859
GPR54 is a G protein-coupled receptor (GPCR) which was formerly an orphan receptor. Recent functional study of GPR54 revealed that the receptor has an essential role to modulate sex-hormones including GnRH. Though antagonists of GPR54 are expected to be novel drugs for sex-hormone dependent diseases such as prostate cancer or endometriosis, small molecule GPR54 antagonists have not been reported. We have synthesized a series of 2-acylamino-4,6-diphenylpyridines to identify potent GPR54 antagonists. Detailed structure–activity relationship studies led to compound 9l with an IC50 value of 3.7 nM in a GPR54 binding assay, and apparent antagonistic activity in a cellular functional assay. 相似文献
3.
Josep Bonjoch Faïza Diaba Lluís Pagès Daniel Pérez Lidia Soca Montserrat Miralpeix Dolors Vilella Paquita Anton Carles Puig 《Bioorganic & medicinal chemistry letters》2009,19(15):4299-4302
A γ-carboline series of cysLT1 receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds. 相似文献
4.
Kohsuke Asoh Masami Kohchi Ikumi Hyoudoh Tatsuo Ohtsuka Miyako Masubuchi Kenichi Kawasaki Hirosato Ebiike Yasuhiko Shiratori Takaaki A. Fukami Osamu Kondoh Toshiyuki Tsukaguchi Nobuya Ishii Yuko Aoki Nobuo Shimma Masahiro Sakaitani 《Bioorganic & medicinal chemistry letters》2009,19(6):1753-1757
A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC50 = 1.1 nM) and antitumor activity in human cancer xenografts in mice. 相似文献
5.
Tao M Raddatz R Aimone LD Hudkins RL 《Bioorganic & medicinal chemistry letters》2011,21(20):6126-6130
Three series of novel 4,5-fused pyridazinones were synthesized as histamine H(3) receptor antagonists. The 2,5,6,7-tetrahydrocyclopenta[d]pyridazin-1-one 5q and 5,6,7,8-tetrahydro-2H-phthalazin-1-one 5u displayed high affinity at both rat and human H(3) receptors, and showed potent antagonist and full inverse agonist activity in functional assays. 相似文献
6.
Pauline C. Ting Joe F. Lee Margaret M. Albanese Jie Wu Robert Aslanian Leonard Favreau Cymbelene Nardo Walter A. Korfmacher Robert E. West Shirley M. Williams John C. Anthes Maria A. Rivelli Michel R. Corboz John A. Hey 《Bioorganic & medicinal chemistry letters》2010,20(17):5004-5008
A structure–activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H3) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i–k with Ki ? 0.5 nM and good in vivo activity. 相似文献
7.
Muthusamy Venkatraj Kevin K. Ariën Jan Heeres Jurgen Joossens Jonas Messagie Johan Michiels Pieter Van der Veken Guido Vanham Paul J. Lewi Koen Augustyns 《Bioorganic & medicinal chemistry letters》2012,22(23):7174-7178
This letter reports the synthesis and structure–activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains. 相似文献
8.
Wen-Shan Li Shivaji V. More Chie-Hong Wang Ya Ching Jen Ching-Fa Yao Tein-Fu Wang Chin-Chun Hung Shu-Chuan Jao 《Bioorganic & medicinal chemistry letters》2010,20(3):1148-1152
This study describes the synthesis and structure–activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect. 相似文献
9.
Makoto Ishikawa Takeshi Furuuchi Miki Yamauchi Fumikazu Yokoyama Nobukazu Kakui Yasuo Sato 《Bioorganic & medicinal chemistry》2010,18(14):5441-5448
4-((1H-Imidazol-4-yl)methyl)-1-aryl-piperazine and piperidine derivatives were designed and synthesized as candidate human histamine type 3 agonists. The piperazine derivatives were found to have low (or no) affinity for human histamine H3 receptor, whereas the piperidine derivatives showed moderate to high affinity, and their agonistic activity was greatly influenced by substituents on the aromatic ring. Among the piperidine-containing compounds, 17d and 17h were potent human histamine H3 receptor agonists with high selectivity over the closely related human H4 receptor. Our results indicate that appropriate conformational restriction, that is, by the piperidine spacer moiety, favors specific binding to the human histamine H3 receptor. 相似文献
10.
John L. Gilmore James E. Sheppeck Jim Wang T.G. Murali Dhar Cullen Cavallaro Arthur M. Doweyko Lorraine Mckay Mark D. Cunningham Sium F. Habte Steven G. Nadler John H. Dodd John E. Somerville Joel C. Barrish 《Bioorganic & medicinal chemistry letters》2013,23(19):5448-5451
SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. 相似文献
11.
《Bioorganic & medicinal chemistry letters》2014,24(21):5111-5117
Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure–kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs. 相似文献
12.
Ashwin U. Rao Anandan Palani Xiao Chen Ying Huang Robert G. Aslanian Robert E. West Shirley M. Williams Ren-Long Wu Joyce Hwa Christopher Sondey Jean Lachowicz 《Bioorganic & medicinal chemistry letters》2009,19(21):6176-6180
A series of 2-(1,4′-bipiperidine-1′-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H3 receptor antagonists. Introduction of diversity at the 6-position of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure–activity relationships for these new thiazolopyridine antagonists are discussed. 相似文献
13.
《Bioorganic & medicinal chemistry letters》2014,24(17):4254-4259
Neuropilins (NRPs) are VEGF-A165 co-receptors over-expressed in tumor cells, and considered as targets in angiogenic-related pathologies. We previously identified compound 1, the first non-peptidic antagonist of the VEGF-A165/NRP binding, which exhibits in vivo anti-angiogenic and anti-tumor activities. We report here the synthesis and biological evaluations of new antagonists structurally-related to compound 1. Among these molecules, 4a, 4c and 4d show cytotoxic effects on HUVEC and MDA-MB-31 cells, and antagonize VEGF-A165/NRP-1 binding. This study confirmed our key structure–activity relationships hypothesis and paved the way to compound 1 ‘hit to lead’ optimization. 相似文献
14.
Marietta Tóth Sándor Kun Éva Bokor Mahmoud Benltifa Gaylord Tallec Sébastien Vidal Tibor Docsa Pál Gergely László Somsák Jean-Pierre Praly 《Bioorganic & medicinal chemistry》2009,17(13):4773-4785
A series of per-O-benzoylated 5-β-d-glucopyranosyl-2-substituted-1,3,4-oxadiazoles was prepared by acylation of the corresponding 5-(β-d-glucopyranosyl)tetrazole. As an alternative, oxidation of 2,6-anhydro-aldose benzoylhydrazones by iodobenzene I,I-diacetate afforded the same oxadiazoles. 1,3-Dipolar cycloaddition of nitrile oxides to per-O-benzoylated β-d-glucopyranosyl cyanide gave the corresponding 5-β-d-glucopyranosyl-3-substituted-1,2,4-oxadiazoles. The O-benzoyl protecting groups were removed by base-catalyzed transesterification. The 1,3,4-oxadiazoles were practically inefficient as inhibitors of rabbit muscle glycogen phosphorylase b while the 1,2,4-oxadiazoles displayed inhibitory activities in the micromolar range. The best inhibitors were the 5-β-d-glucopyranosyl-3-(4-methylphenyl- and -2-naphthyl)-1,2,4-oxadiazoles (Ki = 8.8 and 11.6 μM, respectively). A detailed analysis of the structure–activity relationships is presented. 相似文献
15.
Hiroshi Morita Yuichiro Tomizawa Jun Deguchi Tokio Ishikawa Hiroko Arai Kazumasa Zaima Takahiro Hosoya Yusuke Hirasawa Takayuki Matsumoto Katsuo Kamata Wiwied Ekasari Aty Widyawaruyanti Tutik Sri Wahyuni Noor Cholies Zaini Toshio Honda 《Bioorganic & medicinal chemistry》2009,17(24):8234-8240
Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials. Interactions of parasitized red blood cells (pRBCs) with endothelium in aorta are especially important in the processes contribute to the pathogenesis of severe malaria. Nitric oxide (NO) reduces endothelial expression of receptors/adhesion molecules used by pRBC to adhere to vascular endothelium, and reduces cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 showed vasorelaxation activity against rat aortic ring, which may be related with NO production. A series of a hydroxyl and a nitrogen-substituted derivatives and a dehydroxy derivative of 1 have been synthesized as having potent antimalarials against P. falciparum with vasodilator activity, which may reduce cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 exhibited a potent antimalarial activity and a high selectivity index in vitro, suggesting that the presence of a hydroxyl and a nitrogen atom without any substituents may be important to show antimalarial activity. Relative to cassiarin A, a methoxy derivative showed more potent vasorelaxant activity, although it did not show improvement for inhibition of P. falciparum in vitro. These cassiarin derivatives may be promising candidates as antimalarials with different mode of actions. 相似文献
16.
Ayako Moritomo Hiroyoshi Yamada Toshihiro Watanabe Hirotsune Itahana Shinobu Akuzawa Minoru Okada Mitsuaki Ohta 《Bioorganic & medicinal chemistry》2013,21(24):7841-7852
To identify potent dual 5-HT2B and 5-HT7 receptor antagonists, we synthesized a series of novel carbonyl guanidine derivatives and examined their structure–activity relationships. Among these compounds, N-(9-hydroxy-9H-fluorene-2-carbonyl)guanidine (10) had a good in vitro profile, that is, potent affinity for human 5-HT2B and 5-HT7 receptor subtypes (Ki = 1.8 nM and Ki = 17.6 nM, respectively) and high selectivity over 5-HT2A, 5-HT2C, α1, D2 and M1 receptors. Compound 10 also showed a suppressing effect on 5-HT-induced dural protein extravasation in guinea pigs when orally administered. 相似文献
17.
Yun Suk Lee Hee Kim Young-Ho Kim Eun Joo Roh Hogyu Han Kye Jung Shin 《Bioorganic & medicinal chemistry letters》2012,22(24):7555-7561
A series of thiazole derivatives were designed, and prepared to develop RAGE antagonist for the treatment of Alzheimer’s disease (AD). SAR studies were performed to optimize inhibitory activity on Aβ-RAGE binding. SAR studies showed that introducing an amino group at part A was essential for inhibitory activity on Aβ-RAGE binding. Compounds selected from Aβ-RAGE binding screening displayed inhibitory activity on Aβ transport across BBB. They also showed inhibitory activity against Aβ-induced NF-κB activation. These results indicated that our derivatives had a potential as therapeutic agent for the treatment of AD. 相似文献
18.
Nafizal Hossain Svetlana Ivanova Åsa Sjöholm Timén Jonas Bergare Tesfaledet Mussie Lena Bergström 《Bioorganic & medicinal chemistry letters》2013,23(14):4026-4030
A series of zwitterionic spirocyclic compounds were synthesised. In vitro data revealed that these compounds were potent CCR1 antagonists. In particular, 2, 4, 11 and 20 inhibited CCR1 mediated chemotaxis of THP-1 cells in a functional assay. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(22):5284-5287
Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure–activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b–c and 6a–b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10 mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold. 相似文献
20.
Chao Gao Ting-Hong Ye Ning-Yu Wang Xiu-Xiu Zeng Li-Dan Zhang Ying Xiong Xin-Yu You Yong Xia Ying Xu Cui-Ting Peng Wei-Qiong Zuo Yuquan Wei Luo-Ting Yu 《Bioorganic & medicinal chemistry letters》2013,23(17):4919-4922
N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study. 相似文献