52315-08-9Relevant academic research and scientific papers
SMALL MOLECULE ANTAGONIST COMPOUND TAC5 SERIES HAVING TOLL-LIKE RECEPTOR 3/7/8/9 INHIBITORY FUNCTION
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Paragraph 0112-0115, (2021/07/17)
A small molecule antagonist compound having a toll-like receptor 3/7/8/9 inhibitory function and its use in inhibiting TLR7, TLR8, TLR9 and TLR3 are disclosed. A novel compound expressed by TAC5 and TAC5-a, TAC5-c, TAC5-d or TAC5-e which are derivatives thereof not only prevents TNFα secretion, NFkB activation, IkB degradation and MAPKs phosphorylation induced by poly(I:C) (TLR3 agonist), IMQ (TLR7 agonist), CL075 (TLR7/8 agonist), R848 (TLR7/8 agonist), TL8 (TLR8 agonist) or CpG ODN (TLR9 agonist), but also inhibits generation of inflammatory cytokine, and thus is highly advantageous for preventive or therapeutic use for TLR3/7/8/9-related autoimmune diseases and inflammatory diseases including systemic lupus erythematosus, psoriasis and the like.
SECOND GENERATION GRP94-SELECTIVE INHIBITORS
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Paragraph 0103; 0104; 0105, (2019/03/12)
The present technology provides compounds selective for the Grp94 isoform, as well as compositions including such compounds, that are useful for treatment of multiple myeloma, melanoma, lung cancer, hepatocellular carcinoma, breast cancer, prostate cancer
Probing the Hydrophobic Binding Pocket of G-Protein-Coupled Lysophosphatidylserine Receptor GPR34/LPS1 by Docking-Aided Structure-Activity Analysis
Sayama, Misa,Inoue, Asuka,Nakamura, Sho,Jung, Sejin,Ikubo, Masaya,Otani, Yuko,Uwamizu, Akiharu,Kishi, Takayuki,Makide, Kumiko,Aoki, Junken,Hirokawa, Takatsugu,Ohwada, Tomohiko
supporting information, p. 6384 - 6399 (2017/08/02)
The ligands of certain G-protein-coupled receptors (GPCRs) have been identified as endogenous lipids, such as lysophosphatidylserine (LysoPS). Here, we analyzed the molecular basis of the structure-activity relationship of ligands of GPR34, one of the LysoPS receptor subtypes, focusing on recognition of the long-chain fatty acid moiety by the hydrophobic pocket. By introducing benzene ring(s) into the fatty acid moiety of 2-deoxy-LysoPS, we explored the binding site's preference for the hydrophobic shape. A tribenzene-containing fatty acid surrogate with modifications of the terminal aromatic moiety showed potent agonistic activity toward GPR34. Computational docking of these derivatives with a homology modeling/molecular dynamics-based virtual binding site of GPR34 indicated that a kink in the benzene-based lipid surrogates matches the L-shaped hydrophobic pocket of GPR34. A tetrabenzene-based lipid analogue bearing a bulky tert-butyl group at the 4-position of the terminal benzene ring exhibited potent GPR34 agonistic activity, validating the present hydrophobic binding pocket model.
Identification of the Privileged Position in the Imidazo[1,2-a]pyridine Ring of Phosphonocarboxylates for Development of Rab Geranylgeranyl Transferase (RGGT) Inhibitors
Ka?mierczak, Aleksandra,Kusy, Damian,Niinivehmas, Sanna P.,Gmach, Joanna,Joachimiak, ?ukasz,Pentik?inen, Olli T.,Gendaszewska-Darmach, Edyta,B?azewska, Katarzyna M.
supporting information, p. 8781 - 8800 (2017/11/15)
Members of the Rab GTPase family are master regulators of vesicle trafficking. When disregulated, they are associated with a number of pathological states. The inhibition of RGGT, an enzyme responsible for post-translational geranylgeranylation of Rab GTPases represents one way to control the activity of these proteins. Because the number of molecules modulating RGGT is limited, we combined molecular modeling with biological assays to ascertain how modifications of phosphonocarboxylates, the first reported RGGT inhibitors, rationally improve understanding of their structure-activity relationship. We have identified the privileged position in the core scaffold of the imidazo[1,2-a]pyridine ring, which can be modified without compromising compounds' potency. Thus modified compounds are micromolar inhibitors of Rab11A prenylation, simultaneously being inactive against Rap1A/Rap1B modification, with the ability to inhibit proliferation of the HeLa cancer cell line. These findings were rationalized by molecular docking, which recognized interaction of phosphonic and carboxylic groups as decisive in phosphonocarboxylate localization in the RGGT binding site.
Second Generation Grp94-Selective Inhibitors Provide Opportunities for the Inhibition of Metastatic Cancer
Crowley, Vincent M.,Huard, Dustin J. E.,Lieberman, Raquel L.,Blagg, Brian S. J.
supporting information, p. 15775 - 15782 (2017/11/14)
Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum (ER) resident isoform of the 90 kDa heat shock protein (Hsp90) family and its inhibition represents a promising therapeutic target for the treatment of many diseases. Modification of the first generation cis-amide bioisostere imidazole to alter the angle between the resorcinol ring and the benzyl side chain via cis-amide replacements produced compounds with improved Grp94 affinity and selectivity. Structure–activity relationship studies led to the discovery of compound 30, which exhibits 540 nm affinity and 73-fold selectivity towards Grp94. Grp94 is responsible for the maturation and trafficking of proteins associated with cell signaling and motility, including select integrins. The Grp94-selective inhibitor 30 was shown to exhibit potent anti-migratory effects against multiple aggressive and metastatic cancers.
Probing the Azaaurone Scaffold against the Hepatic and Erythrocytic Stages of Malaria Parasites
Carrasco, Marta P.,Machado, Marta,Gon?alves, Lídia,Sharma, Moni,Gut, Jiri,Lukens, Amanda K.,Wirth, Dyann F.,André, Vania,Duarte, Maria Teresa,Guedes, Rita C.,dos Santos, Daniel J. V. A.,Rosenthal, Philip J.,Mazitschek, Ralph,Prudêncio, Miguel,Moreira, Rui
supporting information, p. 2194 - 2204 (2016/10/19)
The potential of azaaurones as dual-stage antimalarial agents was investigated by assessing the effect of a small library of azaaurones on the inhibition of liver and intraerythrocytic lifecycle stages of the malaria parasite. The whole series was screened against the blood stage of a chloroquine-resistant Plasmodium falciparum strain and the liver stage of P. berghei, yielding compounds with dual-stage activity and sub-micromolar potency against erythrocytic parasites. Studies with genetically modified parasites, using a phenotypic assay based on the P. falciparum Dd2-ScDHODH line, which expresses yeast dihydroorotate dehydrogenase (DHODH), showed that one of the azaaurone derivatives has the potential to inhibit the parasite mitochondrial electron-transport chain. The global urgency in finding new therapies for malaria, especially against the underexplored liver stage, associated with chemical tractability of azaaurones, warrants further development of this chemotype. Overall, these results emphasize the azaaurone chemotype as a promising scaffold for dual-stage antimalarials.
N-(2-ARYLETHYL) BENZYLAMINES AS ANTAGONISTS OF THE 5-HT6 RECEPTOR
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Paragraph 0137, (2016/01/25)
The present invention relates to the use compounds of formula I which are antagonists of the 5-HT 6 receptor, for treating a cognitive disorder selected from the group consisting of age-related cognitive decline, mild cognitive impairment and dementia
Design and synthesis of l- and d-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase
Patel, Bhargav A.,Krishnan, Ramalingam,Khadtare, Nikhil,Gurukumar,Basu, Amartya,Arora, Payal,Bhatt, Aaditya,Patel, Maulik R.,Dana, Dibyendu,Kumar, Sanjai,Kaushik-Basu, Neerja,Talele, Tanaji T.
, p. 3262 - 3271 (2013/07/05)
Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 μM) and 2 (IC50 = 10.6 μM) as represented by hybrid compound 27 (IC 50 = 6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC50 = 19.3 μM) and 45 (IC50 = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition.
ANTI-BACTERIAL COMPOSITIONS AND METHODS INCLUDING TARGETING VIRULENCE FACTORS OF STAPHYLOCOCCUS AUREUS
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Page/Page column 31, (2012/02/03)
This disclosure relates to compositions and methods including for the inhibition, prevention, and/or treatment of microbial infections, including infections from such pathogens as Staphylococcus aureus.
Phosphonosulfonates are potent, selective inhibitors of dehydrosqualene synthase and staphyloxanthin biosynthesis in staphylococcus aureus
Song, Yongcheng,Lin, Fu-Yang,Yin, Fenglin,Hensler, Mary,Poveda, Carlos A. Rodrígues,Mukkamala, Dushyant,Cao, Rong,Wang, Hong,Morita, Craig T.,Pacanowska, Dolores González,Nizet, Victor,Oldfield, Eric
experimental part, p. 976 - 988 (2009/12/04)
Staphylococcus aureus produces a golden carotenoid virulence factor called staphyloxanthin (STX), and we report here the inhibition of the enzyme, dehydrosqualene synthase (CrtM), responsible for the first committed step in STX biosynthesis. The most acti
