Bioorganic & Medicinal Chemistry Letters 2012-10-01

Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

Yevgeni Besidski, William Brown, Johan Bylund, Michael Dabrowski, Sophie Dautrey, Magali Harter, Lucy Horoszok, Yin Hu, Dean Johnson, Shawn Johnstone, Paul Jones, Sandrine Leclerc, Karin Kolmodin, Inger Kers, Maryse Labarre, Denis Labrecque, Jennifer Laird, Therese Lundström, John Martino, Mickaël Maudet, Alexander Munro, Martin Nylöf, Andrea Penwell, Didier Rotticci, Andis Slaitas, Anna Sundgren-Andersson, Mats Svensson, Gitte Terp, Huascar Villanueva, Christopher Walpole, Ronald Zemribo, Andrew M Griffin

文献索引：Bioorg. Med. Chem. Lett. 22(19) , 6205-11, (2012)

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摘要

Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.Copyright © 2012 Elsevier Ltd. All rights reserved.