- Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease
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Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT6R) antagonists resulted in identification of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HT6R (Ki = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion channels, steroids, immunological factors, second messengers, and prostaglandins. It has high selectivity over 5-HT2A receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of 5al, donepezil, and memantine (triple combination) produces synergistic effects in extracellular levels of acetylcholine in the ventral hippocampus. Preclinical efficacy in triple combination and high selectivity over 5-HT2A receptors are the differentiating features which culminated in selection of 5al for further development. The Phase-1 evaluation of safety and pharmacokinetics has been completed, allowing for the initiation of a Phase-2 proof of concept study.
- Nirogi, Ramakrishna,Shinde, Anil,Kambhampati, Rama Sastry,Mohammed, Abdul Rasheed,Saraf, Sangram Keshari,Badange, Rajesh kumar,Bandyala, Thrinath Reddy,Bhatta, Venugopalarao,Bojja, Kumar,Reballi, Veena,Subramanian, Ramkumar,Benade, Vijay,Palacharla, Raghava Choudary,Bhyrapuneni, Gopinadh,Jayarajan, Pradeep,Goyal, Vinod,Jasti, Venkat
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p. 1843 - 1859
(2017/03/17)
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- Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators
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Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes. In spite of the theoretical potential of CB1 NAMs, published in vivo studies have generally not been able to demonstrate the expected therapeutically-relevant CB1-mediated effects. Thus, a greater range of molecular tools are required to allow definitive elucidation of the effects of CB1 allosteric modulation. In this study, we show a novel series of indole sulfonamides. Compounds 5e and 6c (ABD1075) had potencies of 4 and 3?nM respectively, and showed good oral exposure and CNS penetration, making them highly versatile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.
- Greig, Iain R.,Baillie, Gemma L.,Abdelrahman, Mostafa,Trembleau, Laurent,Ross, Ruth A.
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p. 4403 - 4407
(2016/08/25)
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- COMPOSITIONS AND METHODS FOR TARGETING RECEPTORS EXPRESSED IN THE GUT
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The invention relates to novel compounds and pharmaceutical preparations thereof, as well as methods of making and using these compounds. The invention further relates to methods of treating or preventing disease using the novel compounds of the invention
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Page/Page column 41; 42
(2016/02/09)
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- Iron(II)-catalyzed asymmetric intramolecular aminohydroxylation of indoles
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An enantioselective intramolecular indole aminohydroxylation reaction is catalyzed by iron(II)-chiral bisoxazoline (BOX) complexes (ee up to 99%, dr > 20:1). This discovery enables expedient asymmetric synthesis of a series of biologically active 3-amino
- Zhang, Yong-Qiang,Yuan, Yong-An,Liu, Guan-Sai,Xu, Hao
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p. 3910 - 3913
(2013/09/02)
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- N-ARYLSULFONYL-3-SUBSTITUTED INDOLES HAVING SEROTONIN RECEPTOR AFFINITY, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
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The present invention relates to novel N-arylsulfonyl-3-substituted indole compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their geometric forms, their N-oxides, their polymorphs, their pharmaceutically acceptable
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- Halogen-magnesium exchange reaction of iodoindole derivatives
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Halogen-magnesium exchange reaction of iodoindoles with ethylmagnesium bromide in THF undergoes smoothly to give indolylmagnesium bromides which react with various electrophiles.
- Kondo, Yoshinori,Yoshida, Akihiro,Sato, Shuichiroh,Sakamoto, Takao
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p. 105 - 108
(2007/10/02)
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- Intramolecular rhodium carbenoid insertions into aromatic C-H bonds. Preparation of 1,3-dihydrothiophene 2,2-dioxides fused onto aromatic rings
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The preparation of 1-carboalkoxy-1,3-dihydrobenzenothiophene 2,2-dioxides via rhodium acetate or rhodium trifluoro-acetate catalyzed decomposition of α-diazo-β-arylmethanesulfonyl esters is described.The reaction has been extended to yield 1,3-dihydrothiophene 2,2-dioxides fused to the 2,3 position of thiophene and indole, but not of furans.In the latter case products derived from the opening of the furan ring were obtained.Key words: synthesis, 1-carboalkoxy-1,3-dihydrobenzothiophene 2,2-dioxides, intramolecular carbenoid insertions, rhodium acetate catalysis.
- Babu, Suresh D.,Hrytsak, Michael D.,Durst, Tony
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p. 1071 - 1076
(2007/10/02)
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- 4-(PHENYLSULFONYL)-4H-FUROINDOLE - A STABLE SYNTHETIC ANALOGUE OF INDOLE-2,3-QUINODIMETHANE
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The N-phenylsulfonyl derivate (2) of the previously unknown fused heterocycle 4H-furo indole is synthesized from indole-3-carboxaldehyde (3) in 28percent yield and undergoes a Diels-Alder reaction with benzyne to give 5H-benzocarbazole (11) in 33percent yield after deoxygenation and deprotection.
- Saulnier, Mark G.,Gribble, Gordon W.
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p. 5435 - 5438
(2007/10/02)
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