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Article

Benzodioxoles: Novel Cannabinoid-1 Receptor Inverse Agonists for the Treatment of Obesity

Supporting Info

Leo Alig, Jochem Alsenz, Mirjana Andjelkovic, Stefanie Bendels, Agnès Bénardeau, Konrad Bleicher, Anne Bourson, Pascale David-Pierson, Wolfgang Guba, Stefan Hildbrand, Dagmar Kube, Thomas Lübbers, Alexander V. Mayweg, Robert Narquizian, Werner Neidhart, Matthias Nettekoven, Jean-Marc Plancher*, Cynthia Rocha, Mark Rogers-Evans, Stephan Röver, Gisbert Schneider, Sven Taylor and Pius Waldmeier

F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, B092/4.18C, CH-4070 Basel, Switzerland

J. Med. Chem., 2008, 51 (7), pp 2115–2127

DOI: 10.1021/jm701487t

Publication Date (Web): March 13, 2008

* To whom correspondence should be addressed. Tel: 41 61 68 86 725 . Fax: 41 61 68 88 714. E-mail: jean-marc.plancher@roche.com.

Abstract

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague−Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure−activity relationships, ultimately leading to the identification of (+)-[(R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone (R)-14g. Biochemical, pharmacokinetic, and pharmacodynamic characteristics of (R)-14g are discussed.

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Published In Issue April 10, 2008
Article ASAPMarch 13, 2008
Received: November 29, 2007

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Article

Benzodioxoles: Novel Cannabinoid-1 Receptor Inverse Agonists for the Treatment of Obesity

Abstract

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History

Recommend & Share

Related Content

Conformational Analysis and Receptor Docking of N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (Taranabant, MK-0364), a Novel, Acyclic Cannabinoid-1 Receptor Inverse Agonist

Identification of Novel Cannabinoid CB1 Receptor Antagonists by Using Virtual Screening with a Pharmacophore Model

Discovery of a New Class of Potent, Selective, and Orally Bioavailable CRTH2 (DP2) Receptor Antagonists for the Treatment of Allergic Inflammatory Diseases

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