82258-51-3Relevant academic research and scientific papers
Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18
Schoeder, Clara T.,Kaleta, Maria,Mahardhika, Andhika B.,Olejarz-Maciej, Agnieszka,?a?ewska, Dorota,Kie?-Kononowicz, Katarzyna,Müller, Christa E.
, p. 381 - 397 (2018/06/14)
GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date. Analogs were synthesized that exhibit broad modifications of the heterocyclic core and/or variation of substituents at the benzylidene moiety. The compounds were investigated in β-arrestin recruitment assays as inhibitors of human GPR18 activation by tetrahydrocannabinol (THC). Selectivity was assessed versus the cannabinoid receptors (CB1 and CB2) and versus GPR55, another orphan GPCR that interacts with cannabinoids. Phenyloxyalkyloxy-substituted benzylidenethiazinones with long alkyl chains (optimal length: hexamethylene) efficiently blocked GPR18 with similarly high potency as lead structure 5. (Z)-2-(3-(6-(4-Chlorophenoxy)hexyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB-27, 23) exhibited the best profile: it displayed an IC50 value of 650 nM at GPR18 and showed improved selectivity versus CB receptors as compared to lead structure 5. Importantly, in contrast to 5, which showed only partial inhibition (60%), 23 led to a complete blockade of THC-induced GPR18 activation and is thus a superior tool for target validation. In addition, several compounds, e.g. 18 and 22, were identified as dual GPR18/GPR55 antagonists with similar potency at both targets, and selectivity versus CB receptors.
Chlorophenoxy aminoalkyl derivatives as histamine H3R ligands and antiseizure agents
Kuder, Kamil,?azewska, Dorota,Latacz, Gniewomir,Schwed, Johannes Stephan,Karcz, Tadeusz,Stark, Holger,Karolak-Wojciechowska, Janina,Kie?-Kononowicz, Katarzyna
, p. 53 - 72 (2015/12/31)
A series of twenty new chlorophenoxyalkylamine derivatives (9-28) was synthesized and evaluated on their binding properties at the human histamine H3 receptor (hH3R). The spacer alkyl chain contained five to seven carbon atoms. The h
Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX
Chambers, Janice E.,Chambers, Howard W.,Funck, Kristen E.,Meek, Edward C.,Pringle, Ronald B.,Ross, Matthew K.
, p. 154 - 159 (2016/12/06)
Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in?vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2?h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in?vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.
Synthesis and biological evaluation of vinyl ether-containing azole derivatives as inhibitors of Trichophyton rubrum
Wang, Lulu,Yang, Wenge,Wang, Kai,Zhu, Jing,Shen, Fei,Hu, Yonghong
scheme or table, p. 4887 - 4890 (2012/08/07)
In an attempt to search for many target compounds with excellent activities, a series of vinyl ether-containing azole derivatives were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against Trichophyton rubrum in vitro indicated that most of the synthesized compounds showed excellent activities. In comparison with fluconazole, itraconazole, voriconazole, omoconazole and amphotericin B, several compounds (such as 7d, 7g and 7h) exhibited more potent inhibitory activities, suggesting that they were promising leads for the development of novel antifungal agents.
Expeditious synthesis and biological evaluation of novel 2,N 6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as potential antimalarials
Gravestock, David,Rousseau, Amanda L.,Lourens, Anna C.U.,Moleele, Simon S.,Van Zyl, Robyn L.,Steenkamp, Paul A.
experimental part, p. 2022 - 2030 (2011/06/21)
A small set of novel 2,N6-disubstituted 1,2-dihydro-1,3,5- triazine-4,6-diamines was prepared possessing a flexible tether between the exocyclic nitrogen bonded to C-6 of the 1,2-dihydro-1,3,5-triazine-4,6-diamine heterocycle and the distal ary
Design, synthesis, and anti-HCV activity of thiourea compounds
Kang, Iou-Jiun,Wang, Li-Wen,Lee, Chung-Chi,Lee, Yen-Chun,Chao, Yu-Sheng,Hsu, Tsu-An,Chern, Jyh-Haur
scheme or table, p. 1950 - 1955 (2009/11/30)
A series of thiourea derivatives were synthesized and their antiviral activity was evaluated in a cell-based HCV subgenomic replicon assay. SAR studies revealed that the chain length and the position of the alkyl linker largely influenced the in vitro anti-HCV activity of this class of potent antiviral agents. Among this series of compounds synthesized, the thiourea derivative with a six-carbon alkyl linker at the meta-position of the central phenyl ring (10) was identified as the most potent anti-HCV inhibitor (EC50 = 0.047 μM) with a selectivity index of 596.
Design, synthesis, antibacterial and QSAR studies of benzimidazole and imidazole chloroaryloxyalkyl derivatives
Khalafi-Nezhad,Soltani Rad,Mohabatkar,Asrari,Hemmateenejad
, p. 1931 - 1938 (2007/10/03)
In view of obtaining some potential antibacterial compounds, we have described synthesis of some chloroaryloxyalkyl imidazole and benzimidazole derivatives. The relevant step in the synthetic sequence was the initial condensation of 4-chloro or 2,4-dichlorophenol with 1, n-dibromoalkanes (n = 2, 4, 5) to provide compounds 3a-f in sufficient yields. The subsequent condensation of 3a-f with some imidazole derivatives and benzimidazole afforded products 4a-l and 5a-e in good yields. Some of compounds 4a-l as well as 5a-e were tested in vitro against Salmonella typhi O-901 and Staphylococcus aureus A 15091. Compounds 4a and 4c showed considerable bactericidal activities against tested bacteria. Compound 4b showed significant activity against S. aureus A 15091 but was inactive against S. typhi O-901. Other compounds showed intermediate activities against S. aureus A 15091 but most of them were inactive against S. typhi O-901. Semiempirical AM1 calculations showed that negative electrostatic potentials around oxygen of the phenoxy and nitrogen of the imidazole moieties have direct effect on the antibacterial activity towards S. aureus A 15091. In QSAR analysis, different electronic, topologic, functional groups and physicochemical descriptors were calculated for each molecule and a three parametric equation was found between the log MIC and HOMO energy, hydration energy and number of primary carbon atoms of the molecules.
Carboxylic acids and skeletal muscle chloride channel conductance: Effects on the biological activity induced by the introduction of an aryloxyalkyl group α to the carboxylic function of 4-chloro-phenoxyacetic acid
Carbonara, Giuseppe,Fracchiolla, Giuseppe,Loiodice, Fulvio,Tortorella, Paolo,Conte-Camerino, Diana,De Luca, Annamaria,Liantonio, Antonella
, p. 749 - 754 (2007/10/03)
2-(4-Chloro-phenoxy)propanoic and 2-(4-chloro-phenoxy)butanoic acids are compounds known to block chloride membrane conductance in rat striated muscle by interaction with a specific receptor. In the present study, a series of chiral analogues has been prepared and tested to evaluate the influence of a second aryloxy moiety introduced in the side-chain at a variable distance from the stereogenic centre. The results show that this chemical modification is detrimental for biological activity which, however, is increased by lengthening the alkyl chain up to three methylenic groups, then decreases to remain constant in the next analogues of the series. A possible explanation for this is proposed on the basis of steric effects and/or different approach of the molecules to the receptor.
BENZOIC ACID COMPOUNDS AND USE THEREOF AS MEDICAMENTS
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, (2008/06/13)
Benzoic acid compounds of the formula STR1 wherein each symbol is as defined in the specification, optical isomers thereof and pharmaceutically acceptable salts thereof; pharmaceutical composition comprising this compound and pharmaceutically acceptable additive; and serotonin 4 receptor agonists, gastrointestinal prokinetic agents and therapeutic agents for various gastrointestinal diseases, which comprise this compound as active ingredient. The compounds of the present invention have high and selective affinity for serotonin 4 receptor, and show agonistic effects thereon. Accordingly, they are useful medications for the prophylaxis and treatment of various gastrointestinal diseases, central nervous disorders, cardiac function disorders, urinary diseases, and the like, as well as useful anti-nociceptors for analgesic use which increase threshold of pain.
BENZOIC ACID COMPOUNDS AND MEDICINAL USE THEREOF
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, (2008/06/13)
A benzoic acid compound of the formula wherein each symbol is as defined in the specification, an optical isomer thereof and a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising this compound and a pharmaceutically acceptable additive, a serotonin 4 receptor agonist comprising this compound as an active ingredient, a gastrointestinal prokinetic agent and a therapeutic agent for gastrointestinal diseases. The compound of the present invention shows selective and high affinity for serotonin 4 receptors, activates same, is useful as a pharmaceutical agent for the prophylaxis and treatment of gastrointestinal diseases (e.g., reflux esophagitis; gastroesophageal reflux such as that accompanying cystic fibrosis; Barrett syndrome; intestinal pseudoileus; acute or chronic gastritis; gastric or duodenal ulcer; Crohn's disease; non-ulcer dyspepsia; ulcerative colitis; postgastrectomy syndrome; postoperative digestive function failure; delayed gastric emptying caused by gastric neurosis, gastroptosis, diabetes, and the like; gastrointestinal disorders such as indigestion, meteorism, abdominal indefinite complaint, and the like; constipation such as atonic constipation, chronic constipation, and that caused by spinal cord injury, pelvic diaphragm failure and the like; and irritable bowel syndrome), central nervous disorders (e.g., schizophrenia, depression, anxiety, disturbance of memory and dementia), cardiac function disorders (e.g., cardiac failure and myocardial ischemia), urinary diseases (e.g., dysuria caused by urinary obstruction, ureterolith, prostatomegaly, spinal cord injury, pelvic diaphragm failure, etc.), and shows superior absorption.
