共查询到20条相似文献,搜索用时 140 毫秒
1.
Nicholas Stock Christopher Baccei Gretchen Bain Charles Chapman Lucia Correa Janice Darlington Christopher King Catherine Lee Daniel S. Lorrain Pat Prodanovich Angelina Santini Kevin Schaab Jilly F. Evans John H. Hutchinson Peppi Prasit 《Bioorganic & medicinal chemistry letters》2010,20(15):4598-4601
AM643 (compound 6, 3-{3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid) was identified as a potential candidate for formulation as a topical agent for the treatment of skin disorders involving leukotriene production. Dermal application of 6 using a prototypical vehicle in a murine ear arachidonic acid model showed significant reduction in the concentrations of leukotrienes in mouse skin with concomitant reduction in ear swelling. 相似文献
2.
《Bioorganic & medicinal chemistry》2014,22(2):692-702
Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration. 相似文献
3.
Yoshikazu Uto Yohei Kiyotsuka Yuko Ueno Yuriko Miyazawa Hitoshi Kurata Tsuneaki Ogata Tsuneo Deguchi Makiko Yamada Nobuaki Watanabe Masahiro Konishi Nobuya Kurikawa Toshiyuki Takagi Satoko Wakimoto Keita Kono Jun Ohsumi 《Bioorganic & medicinal chemistry letters》2010,20(2):746-754
Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3 mg/kg) in our preliminary analysis. 相似文献
4.
The 13C.n.m.r spectra of water-soluble and -insoluble glucans synthesized by enzymes isolated from six strains of Streptococcus mutans are interpreted. The glucans are shown to be composed primarily of α(1→3)- and α-(1→6)-linked glucosyl residues, and the relative abundance of each linkage is estimated from peak areas. Treatment of water-insoluble glucans with dextranase is found to result in water-soluble and -insoluble products, the former enriched in α-(1→6)-linkages and the latter in α-(1→3)-linkages. The structural conclusions arrived at by 13C-n.m.r. spectroscopy are consistent with data from methylation analysis and 1H-n.m.r. spectroscopy. 相似文献
5.
H. B. Lazrek M. Taourirte T. Oulih Y. Kabbaj J. L. Barascut J. L. Imbach 《Nucleosides, nucleotides & nucleic acids》2013,32(7-9):1073-1077
Abstract Synthesis of new 3′-deoxy-3′ and 5′-deoxy-5′-[(4-(purin-9-yl/pyrimidin-1-yl)methyl-1,2,3-Triazol-1-yl]thymidine 8a-g 10a-g from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine and 5′-azido-5′deoxythymidine respectively are described. The key step is the 1,3-dipolar cycloaddition between the azido group and N-9/N-1-propargylpurine/pyrimidine derivatives. 相似文献
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7.
Yusuke Oka Tetsuya Yabuuchi Takahiro Oi Shoichi Kuroda Yasuyuki Fujii Hidenori Ohtake Tomoyuki Inoue Shunichi Wakahara Kayo Kimura Kiyoko Fujita Mayumi Endo Kyoko Taguchi Yoshinori Sekiguchi 《Bioorganic & medicinal chemistry》2013,21(24):7578-7583
Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure–activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase γ (PI3Kγ). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration. 相似文献
8.
《Bioorganic & medicinal chemistry》2014,22(9):2724-2732
A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles 14a–c, 15a–c, 16a, 16b, 19a–d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC50 value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions. 相似文献
9.
Xinbo Zhou Wei Chen Cheng Xu Shiyong Fan Yunde Xie Wu Zhong Lili Wang Song Li 《Bioorganic & medicinal chemistry letters》2010,20(8):2605-2608
A series of novel, potent PPARα/γ dual agonists were synthesized and appraised. The most potent analogue, compound 2b demonstrated EC50 value of 0.012 ± 0.002 and 0.032 ± 0.01 μM, respectively, for hPPARα and hPPARγ in transactivation assay. Additionally, compound 2b demonstrated good glucose and lipid lowering effect in genetic diabetic (db/db) mice. 相似文献
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Nicholas Stock Christopher Baccei Gretchen Bain Alex Broadhead Charles Chapman Janice Darlington Christopher King Catherine Lee Yiwei Li Daniel S. Lorrain Pat Prodanovich Haojing Rong Angelina Santini Jasmine Zunic Jilly F. Evans John H. Hutchinson Peppi Prasit 《Bioorganic & medicinal chemistry letters》2010,20(1):213-217
A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model. 相似文献
12.
Shankar Venkatraman Alec D. Lebsack Kenneth Alves Michael F. Gardner Joyce James Russell B. Lingham Salony Maniar Richard A. Mumford Qian Si Nicholas Stock Kelly M. Treonze Bowei Wang Jasmine Zunic Benito Munoz 《Bioorganic & medicinal chemistry letters》2009,19(19):5803-5806
A series of prolyl-N-isonicotinoyl-(L)-4-aminophenylalanine derivatives substituted at the proline 4-position with cyclic amines was evaluated as VLA-4 antagonists. The ring size and presence or absence of fluorine affected potency and receptor occupancy. The analog with 3,3-difluoropiperidine at the proline 4-position (13) was the most potent compound and had very good duration of receptor occupancy in vitro. The ethyl ester prodrug of 13 demonstrated excellent receptor occupancy after oral dosing in rats. 相似文献
13.
Buzard D Han S Thoresen L Moody J Lopez L Kawasaki A Schrader T Sage C Gao Y Edwards J Barden J Thatte J Fu L Solomon M Liu L Al-Shamma H Gatlin J Le M Xing C Espinola S Jones RM 《Bioorganic & medicinal chemistry letters》2011,21(19):6013-6018
S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists. 相似文献
14.
Jin CH Krishnaiah M Sreenu D Rao KS Subrahmanyam VB Park CY Son JY Sheen YY Kim DK 《Bioorganic & medicinal chemistry》2011,19(8):2633-2640
A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles 14a-e, 15a-e, 17a-c, and 18a-d have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 6-quinolinyl pyrazole analogue 14b inhibited ALK5 phosphorylation with IC(50) value of 0.022 μM and showed 84% inhibition at 0.1 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. 相似文献
15.
《Nucleosides, nucleotides & nucleic acids》2013,32(11):1985-1993
Abstract The synthesis of new 3′-deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine 6a–f, from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine is described. The key step is the 1,3-dipolar cycloaddition between the azido group of the protected AZT 3 and N-1-propargylpyrimidine derivatives 2a–f. All new derivatives 6a–f were evaluated for their inhibitory effects against the replication of HIV-1 (IIIB), HIV-2 (ROD). No marked activity was found. 相似文献
16.
Nagarajan Muthukaman Sanjay Deshmukh Shital Tondlekar Macchindra Tambe Dnyandeo Pisal Neelam Sarode Siddharth Mhatre Samitabh Chakraborti Daisy Shah Vikram M. Bhosale Abhay Kulkarni Mahamad Yunnus A. Mahat Satyawan B. Jadhav Girish S. Gudi Neelima Khairatkar-Joshi Laxmikant A. Gharat 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3766-3773
Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure–activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC50s: <15?nM) along with adequate metabolic stability. Lead compounds 30 and 58 exhibited good exposure and oral bioavailability in mouse pharmacokinetic (PK) study. Compound 30 was selected for further profiling and revealed comparable mouse and rat GSNOR potency, high selectivity against alcohol dehydrogenase (ADH) and carbonyl reductase (CBR1) family of enzymes, low efflux ratio and permeability in PAMPA, a high permeability in CALU-3 assay, significantly low hERG activity and minimal off-target activity. Further, an in vivo efficacy of compound 30 is disclosed in cigarette smoke (CS) induced mouse model for COPD. 相似文献
17.
Hideaki Amada Yoshinori Sekiguchi Naoya Ono Takeshi Koami Tetsuo Takayama Tetsuya Yabuuchi Hironori Katakai Akiko Ikeda Mari Aoki Takumi Naruse Reiko Wada Akiko Nozoe Masakazu Sato 《Bioorganic & medicinal chemistry》2012,20(24):7128-7138
A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50 = 5.5 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50 = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals). 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(6):1605-1610
A series of N′-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide derivatives is synthesized and evaluated for antileishmanial activity against Leishmania donovani promastigotes. Compounds 9a and 9i were shown significant antileishmanial when compared with standard sodium stilbogluconate. Antimicrobial study revealed that compound 9b has potent as well as broad spectrum antibacterial activity when compared with ampicillin and compound 9e showed promising antifungal activity when compared with miconazole. Also, none of the synthesized compounds showed cytotoxicity up to tested concentration. Further, docking study against pteridine reductase 1 enzyme of L. donovani showed good binding interactions. ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2020,30(4):126879
Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. Based on a potent and selective TARP subtype γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its 11C-isotopologue 1 and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo. 相似文献
20.
Jin CH Krishnaiah M Sreenu D Subrahmanyam VB Rao KS Mohan AV Park CY Son JY Sheen YY Kim DK 《Bioorganic & medicinal chemistry letters》2011,21(20):6049-6053
A series of 1-substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrazoles 14a-ae, 16a, 16b, and 21a-c has been prepared and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-(4-methoxyphenyl)-3-(6-methylpyridin-2-yl)-1H-pyrazole-1-carbothioamide (14n) inhibited ALK5 phosphorylation with IC(50) value of 0.57 nM and showed 94% inhibition at 100 nM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. 相似文献