110192-19-3Relevant academic research and scientific papers
Discovery of Inhibitors of the Lipopolysaccharide Transporter MsbA: From a Screening Hit to Potent Wild-Type Gram-Negative Activity
Alexander, Mary Kate,Austin, Cary D.,Dong, Liting,Ho, Hoangdung,Hu, Huiyong,Katakam, Anand K.,Koehler, Michael F. T.,Koth, Christopher M.,Labadie, Sharada S.,Liang, Jun,Miu, Anh,Nishiyama, Mireille,Niu, Yanan,Pang, Jodie,Payandeh, Jian,Reichelt, Michael,Sellers, Benjamin D.,Verma, Vishal A.,Wai, John,Wang, Jian,Wang, Lan,Wang, Qiuyue,Wang, Xinxin,Xu, Yiming,Xu, Zhongya,Zhang, Shuang,Zhang, Yexia
supporting information, (2022/03/02)
The dramatic increase in the prevalence of multi-drug resistant Gram-negative bacterial infections and the simultaneous lack of new classes of antibiotics is projected to result in approximately 10 million deaths per year by 2050. We report on efforts to target the Gram-negative ATP-binding cassette (ABC) transporter MsbA, an essential inner membrane protein that transports lipopolysaccharide from the inner leaflet to the periplasmic face of the inner membrane. We demonstrate the improvement of a high throughput screening hit into compounds with on-target single digit micromolar (μM) minimum inhibitory concentrations against wild-type uropathogenic Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. A 2.98 ? resolution X-ray crystal structure of MsbA complexed with an inhibitor revealed a novel mechanism for inhibition of an ABC transporter. The identification of a fully encapsulated membrane binding site in Gram-negative bacteria led to unique physicochemical property requirements for wild-type activity.
SAR studies of capsazepinoid bronchodilators. Part 1: The importance of the catechol moiety and aspects of the B-ring structure
Dalence-Guzman, Maria F.,Berglund, Magnus,Skogvall, Staffan,Sterner, Olov
, p. 2499 - 2512 (2008/09/21)
Capsazepine as well as its derivatives and analogues are general inhibitors of constriction of human small airways. From a systematic variation of the capsazepine structure, divided into four regions, SARs were established. This part concerns the catechol moiety of the A-ring as well as the 2,3,4,5-tetrahydro-1H-2-azepine moiety (the B-ring) of capsazepine. It is revealed that a conformational constrain (as a fused ring) is important and that compounds with a six-membered B-ring (as a 1,2,3,4-tetrahydroisoquinoline) in general are more potent than the corresponding isoindoline, 2,3,4,5-tetrahydro-1H-2-benzazepine and 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives.
Discovery of novel tetrahydroisoquinoline derivatives as potent and selective factor Xa inhibitors
Ueno, Hiroshi,Yokota, Katsuyuki,Hoshi, Jun-Ichi,Yasue, Katsutaka,Hayashi, Mikio,Uchida, Itsuo,Aisaka, Kazuo,Hase, Yasunori,Katoh, Susumu,Cho, Hidetsura
, p. 185 - 189 (2007/10/03)
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against FXa and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis.
Synthesis and structure-activity relationships of novel selective factor Xa inhibitors with a tetrahydroisoquinoline ring
Ueno, Hiroshi,Yokota, Katsuyuki,Hoshi, Jun-Ichi,Yasue, Katsutaka,Hayashi, Mikio,Hase, Yasunori,Uchida, Itsuo,Aisaka, Kazuo,Katoh, Susumu,Cho, Hidetsura
, p. 3586 - 3604 (2007/10/03)
A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine
Bronchorelaxing compounds
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Page/Page column 15, (2010/02/13)
A compound of the general formula (I) including its pharmaceutically acceptable acid addition salts wherein A is CHR9, wherein R9 is H, C1-C6 alkyl; n is 1-3; B is CHR10, wherein R10 is H, C1-C6 alkyl; m is 1 or 2; D is O or S or optionally NR16, wherein R16 is H, C1-C6 alkyl or C2-C6 acyl; E is CR11R12 or NR13, wherein R11 and R12 are, independent of each other, H or C1-C6 alkyl, R13 is H or C1-C6 alkyl; F is C1-C18 alkyl which may be mono- or di-unsaturated and/or substituted, is useful in treating and preventing pulmonary disease characterized by bronchoconstriction. Also disclosed are pharmaceutical compositions comprising the compound and methods for their manufacture.
Inhibition of phenylethanolamine n-methyltransferase (PNMT) by aromatic hydroxy-substituted 1,2,3,4-tetrahydroisoquinolines: Further studies on the hydrophilic pocket of the aromatic ring binding region of the active site
Sall,Grunewald
, p. 2208 - 2216 (2007/10/02)
In a continuation of studies directed toward characterizing the hydrophilic pocket within the aromatic ring binding region of the active site of phenylethanolamine N-methyltransferase (PNMT), 5-, 6-, 7-, and 8-hydroxy-1,2,3,4-tetrahydroisoquinoline were prepared and evaluated as substates and inhibitors of PNMT. In order to discern the necessity of an acidic hydrogen for interaction at this pocket the corresponding methyl ethers were also evaluated. The enhanced affinity of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (16) versus tetrahydroisoquinoline (13) itself indicates that a hydrophilic pocket exists off of carbon C7 in bound tetrahydroisoquinolines. The diminished affinity of the corresponding methyl ether is consistent with a requirement for the acidic hydrogen of 16 for interaction of the aromatic hydroxyl at site. From the relative activities of the other regioisomeric aromatic hydroxyl-substituted tetrahydroisoquinolines, their corresponding methyl ethers, and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, it appears that the hydrophilic pocket is spatially compact with respect to bound tetrahydroisoquinolines and is surrounded by larger areas of lipophilic character. To allow a comparison of the results of this study with previous data on bound β-phenylethylamines, the methyl ethers of 5-, 6-, 7-, and 8-hydroxy-exo-2-aminobenzonorbornene and of 5- and 6-hydroxy-anti-9-aminobenzonorbornene were also evaluated for their activity as substrates and inhibitors for PNMT. The results of this study are in agreement with previous findings for bound β-phenylethylamines and support the conclusion that the natural substrate for PNMT, norepinephrine, has a different active site binding orientation than most known substrates and competitive inhibitors of the enzyme.
The Preparation and Oxidative Dimerisation of 2-Acetyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline. A New Approach to Tetrahydroisoquinoline Synthesis
Ajao, J. F.,Bird, C. W.
, p. 329 - 331 (2007/10/02)
The title compound has been prepared from 1,2,3,4-tetrahydroisoquinoline via successive nitration, acetylation, reduction and diazotisation.Earlier conflicting reports on the nitration of tetrahydroisoquinoline have been clarified.A better synthetic route
