- A Scalable Method for Regioselective 3-Acylation of 2-Substituted Indoles under Basic Conditions
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Privileged structures such as 2-arylindoles are recurrent molecular scaffolds in bioactive molecules. We here present an operationally simple, high yielding and scalable method for regioselective 3-acylation of 2-substituted indoles under basic conditions
- Johansson, Henrik,Urruticoechea, Andoni,Larsen, Inna,Sejer Pedersen, Daniel
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p. 471 - 481
(2015/08/25)
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- 3-Substituted 2-phenyl-indoles: Privileged structures for medicinal chemistry
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Privileged structures have been used in drug discovery targeting G protein-coupled receptors (GPCR) and other protein classes for more than 20 years. Their rich activity profiles and drug-like characteristics lend themselves to increased productivity in hit identification and lead optimisation. Recently we discovered two allosteric modulators 1 and 2 for the G protein-coupled receptor GPRC6A incorporating the privileged 2-phenyl-indole scaffold, functionalised at the 3-position. In order to develop new potential GPRC6A ligands we engaged in the development of synthetic routes to provide 2-phenyl-indoles with a variety of substituents at the indole 3-position. Herein we describe the development of optimised and efficient synthetic routes to a series of new 2-phenyl-indole building blocks 3 to 9 and show that these can be used to generate a broad variety of 3-substituted 2-phenyl-indoles of interest to medicinal chemists.
- Johansson, Henrik,Jorgensen, Tanja Bogeloov,Gloriam, David E.,Braeuner-Osborne, Hans,Pedersen, Daniel Sejer
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p. 945 - 960
(2013/04/24)
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- Regioselective one pot synthesis of 3,3′-diindolylethylene derivatives and study of their cytotoxic activity
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2,2′-Diphenyl-3,3′-diindolylethylene (DPDIE) derivatives 3a-g were regioselectively prepared in one pot from indoles 1a-g in the presence of Lewis acids and were subsequently evaluated for cytotoxic activity against human leukemic cell lines, U937 and K56
- Mandal, Madhumita,Kumar, Deepak,Roy, Rajneeta,Sen, Rupashree,Das, Padma,Chatterjee, Mitali,Jaisankar, Parasuraman
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supporting information; experimental part
p. 3084 - 3087
(2011/06/24)
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- 3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT2A receptor antagonists
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The development of very high affinity, selective, and bioavailable h5-HT2A receptor antagonists is described. By investigation of the optimal position for the basic nitrogen in a series of 2-phenyl-3-piperidylindoles, it was found that with the basic nitrogen at the 3-position of the piperidine it was not necessary to further substitute the piperidine in order to obtain good binding at h5-HT2A receptors. This meant the compounds no longer had high affinity at the IKr potassium channel, an issue with previous series of 2-aryl-3-(4-piperidyl)indoles. Improvements could be made to oral bioavailability in this series by reduction of the pKa of the basic nitrogen, by adding a fluorine atom to the piperidine ring, leading to 3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (17). Metabolic studies with this compound identified oxidation at the 6-position of the indole as a major route in vitro and in vivo in rats. Blocking this position with a fluorine atom led to 6-fluoro-3-(4-fluoropiperidin-3-yl)-2-phenyl-1H-indole (22), an antagonist with 0.06 nM affinity for h5-HT2A receptors, with bioavailability of 80% and half-life of 12 h in rats.
- Rowley,Hallett,Goodacre,Moyes,Crawforth,Sparey,Patel,Marwood,Patel,Thomas,Hitzel,O'Connor,Szeto,Castro,Hutson,Macleod
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p. 1603 - 1614
(2007/10/03)
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