- The discovery of indole full agonists of the neurotensin receptor 1 (NTSR1)
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Neurotensin (NT) is an endogenous tridecapeptide found in the central nervous system (CNS) and in peripheral tissues. Neurotensin exerts a wide range of physiological effects and it has been found to play a critical role in a number of human diseases, suc
- Di Fruscia, Paolo,He, Yuanjun,Koenig, Marcel,Tabrizifard, Sahba,Nieto, Ainhoa,McDonald, Patricia H.,Kamenecka, Theodore M.
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- Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors
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Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC 50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs 50 > 50 μM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation.
- Yin, Lina,Hu, Qingzhong,Emmerich, Juliette,Lo, Michael Man-Chu,Metzger, Edward,Ali, Amjad,Hartmann, Rolf W.
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p. 5179 - 5189
(2014/07/08)
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- Preparation of functionalized organoindium reagents by means of magnesium insertion into organic halides in the presence of InCl3 at room temperature
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Magnesium, indium, palladium: An efficient one-pot procedure for the direct preparation of triorganoindium reagents from organic halides by means of magnesium insertion in the presence of InCl3 and LiCl is reported (see scheme). The organoindium reagents are obtained in good yields from functionalized aryl, heteroaryl, and alkyl bromides and benzyl chlorides at 25 °C in THF within 4h. Moreover, the resulting organoindium reagents could be efficiently used as reagents in Pd-catalyzed cross-coupling reactions with a wide functional group tolerance. Copyright
- Bernhardt, Sebastian,Shen, Zhi-Liang,Knochel, Paul
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supporting information
p. 828 - 833
(2013/02/23)
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- Room-temperature Suzuki-Miyaura coupling of heteroaryl chlorides and tosylates
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Suzuki-Miyaura coupling of heteroaryls is an important method for the preparation of compound libraries for medicinal chemistry and materials research. Although many catalysts have been developed, none of them have been generally applicable to the coupling reactions of heteroaryl chlorides and tosylates at room temperature. We discovered that a catalyst combination of Pd(OAc)2 and XPhos (2-dicyclohexylphosphanyl-2',4',6'- triisopropylbiphenyl) could efficiently catalyze these couplings. Besides the choice of catalyst, the use of hydroxide bases in an aqueous alcoholic solvent was essential for fast couplings. These conditions promoted fast release of active catalyst (XPhos)Pd0, and accelerated the transmetalation in the catalytic cycle. Most of the major families of heteroaryl chlorides (31 examples) and tosylates (17 examples) reached full conversion within minutes to hours at room temperature. The method could be easily scaled up for gram-scale synthesis. Furthermore, we examined the relative reactivity of coupling partners in whole reactions. Electron-rich heteroaryl chlorides and tosylates reacted more slowly than electron-deficient ones, in the order of indole, pyrrole furan, thiophene > pyridine. Similarly, electron-deficient arylboronic acids were less reactive than electron-neutral and electron-rich ones. The reactivity trends from this study can help to choose appropriate coupling partners for Suzuki reactions.
- Yang, Junfeng,Liu, Sijia,Zheng, Jian-Feng,Zhou, Jianrong
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supporting information
p. 6248 - 6259,12
(2020/09/16)
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- SYNTHESIS OF 5-ARYLATED INDOLES VIA PALLADIUM-CATALYZED CROSS-COUPLING REACTION OF 5-INDOLYLBORONIC ACID WITH ARYL AND HETEROARYL HALIDES
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Palladium(0)-catalyzed cross-coupling reaction of 5-indolylboronic acid with various aryl and heteroaryl halides results in regioselective formation of 5-arylated indoles in good yields.
- Yang, Youhua,Martin, Arnold R.
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p. 1395 - 1398
(2007/10/02)
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