The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.

CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X-ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high-resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX-4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan-CLK inhibition in PMDS.

Ergoline derivative (6aR,9R)-4-(2-(dimethylamino) ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3-fg] quinoline-7(4H)-carboxamide (1), a CXCR3 antagonist, also inhibits human histamine H3 receptors (H3R) and represents a structurally novel H3R inverse agonist chemotype. It displays favorable pharmacokinetic and in vitro safety profiles, and served as a lead compound in a program to explore ergoline derivatives as potential drug candidates for the treatment of narcolepsy. A key objective of this work was to enhance the safety and efficacy profiles of 1, while minimizing its duration of action to mitigate the episodes of insomnia documented with previously reported clinical candidates during the night following administration. Modifications to the ergoline core at positions 1, 6 and 8 were systematically investigated, and derivative 23 (1-((4aR,8R,9aR)-8-(hydroxymethyl)-1-(2-((R)-2-methylpyrrolidin-1-yl) ethyl)-4,4a,7,8,9,9a-hexahydroindolo[1,14-fg]quinolin-6(1H)-yl)ethanone) was identified as a promising lead compound. Derivative 23 has a desirable pharmacokinetic profile and demonstrated efficacy by enhancing brain concentrations of tele-methylhistamine, a major histamine metabolite. This validates the potential of the ergoline scaffold to serve as a template for the development of H3R inverse agonists.

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A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI-MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Abeta in human APP-wildtype transgenic (APP51/16) mice after oral administration.

Studies aimed at preparing (+/-)-strychnofoline by total synthesis are detailed. The route described makes use of a recently developed MgI(2)-mediated ring-expansion reaction of spiro[cyclopropan-1,3'-oxindole] with a cyclic disubstituted aldimine. The ring-expansion product was formed as a single diastereoisomer in 55 % yield, possessing the same stereochemical pattern found in strychnofoline. In addition, our synthetic effort has led to the development of new reaction methodology to access 3,4-disubstituted cyclic aldimines.

An efficient synthesis of the antitumor alkaloid (+/-)-strychnofoline is documented. Key to the development of the highly convergent strategy delineated is the coupling of a cyclic imine with spiro[cyclopropan-1,3'-oxindole], which takes place in a highly diastereoselective manner. The ability to conduct annulation reactions of spirocyclopropyloxindoles with functionalized cyclic imines provides new avenues for the preparation of this important class of biologically active structures.

The role of the bifunctional catalyst is decisive: The magnesium ion as Lewis acid and its nucleophilic iodide counterion contribute in synergy to the successful ring expansion of the cyclopropane 1 by aldimine 2 [Eq. (1)]. This reaction offers a novel route to spiro[pyrrolidin-3,3'-oxindoles] 3.

Angewandte ChemieVolume 111, Issue 21 p. 3379-3381 Zuschrift Eine neuartige Methode zur Synthese von Spiro[pyrrolidin-3,3′-oxindolen]: katalysierte Ringerweiterung von Cyclopropanen mit Aldiminen Phil B. Alper, Phil B. Alper Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich (Schweiz), Fax: (+41) 1-632-13-28Search for more papers by this authorChristiane Meyers, Christiane Meyers Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich (Schweiz), Fax: (+41) 1-632-13-28Search for more papers by this authorAndreas Lerchner, Andreas Lerchner Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich (Schweiz), Fax: (+41) 1-632-13-28Search for more papers by this authorDionicio R. Siegel, Dionicio R. Siegel Arnold and Mabel Beckman Laboratory for Chemical Synthesis, California Institute of Technology, Pasadena, CA 91125, USASearch for more papers by this authorErick M. Carreira, Erick M. Carreira carreira@org.chem.ethz.ch Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich (Schweiz), Fax: (+41) 1-632-13-28Search for more papers by this author Phil B. Alper, Phil B. Alper Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich (Schweiz), Fax: (+41) 1-632-13-28Search for more papers by this authorChristiane Meyers, Christiane Meyers Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich (Schweiz), Fax: (+41) 1-632-13-28Search for more papers by this authorAndreas Lerchner, Andreas Lerchner Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich (Schweiz), Fax: (+41) 1-632-13-28Search for more papers by this authorDionicio R. Siegel, Dionicio R. Siegel Arnold and Mabel Beckman Laboratory for Chemical Synthesis, California Institute of Technology, Pasadena, CA 91125, USASearch for more papers by this authorErick M. Carreira, Erick M. Carreira carreira@org.chem.ethz.ch Laboratorium für Organische Chemie, ETH-Zentrum, Universitätstrasse 16, CH-8092 Zürich (Schweiz), Fax: (+41) 1-632-13-28Search for more papers by this author First published: 26 October 1999 https://doi.org/10.1002/(SICI)1521-3757(19991102)111:21<3379::AID-ANGE3379>3.0.CO;2-JCitations: 53AboutPDF ToolsRequest permissionAdd to favorites ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Die Rolle des bifunktionellen Katalysators ist entscheidend: Das Magnesium-Ion als Lewis-Säure und seine nucleophilen Iodid-Gegenionen wirken zusammen und tragen gemeinsam zur erfolgreichen Ringerweiterung des Cyclopropans 1 mit Aldiminen des Typs 2 bei [Gl. (1)]. Diese Reaktion bietet einen neuartigen Zugang zu Spiro[pyrrolidin-3,3′-oxindolen] 3. Citing Literature Supporting Information Hintergrundinformationen zu diesem Beitrag sind im WWW unter http://www.wiley-vch.de/contents/jc_2001/1999/z13659_s.pdf zu finden oder können beim Autor angefordert werden. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume111, Issue21November 2, 1999Pages 3379-3381 This is the German version of Angewandte Chemie. Note for articles published since 1962: Do not cite this version alone. Take me to the International Edition version with citable page numbers, DOI, and citation export. We apologize for the inconvenience. RelatedInformation