1. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.
- Author
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Besidski Y, Brown W, Bylund J, Dabrowski M, Dautrey S, Harter M, Horoszok L, Hu Y, Johnson D, Johnstone S, Jones P, Leclerc S, Kolmodin K, Kers I, Labarre M, Labrecque D, Laird J, Lundström T, Martino J, Maudet M, Munro A, Nylöf M, Penwell A, Rotticci D, Slaitas A, Sundgren-Andersson A, Svensson M, Terp G, Villanueva H, Walpole C, Zemribo R, and Griffin AM
- Subjects
- Amides administration & dosage, Amides chemistry, Animals, Benzothiazoles administration & dosage, Benzothiazoles chemistry, Disease Models, Animal, Dose-Response Relationship, Drug, Humans, Inflammation drug therapy, Molecular Structure, Rats, Recombinant Proteins antagonists & inhibitors, Solubility, Structure-Activity Relationship, Amides pharmacology, Benzothiazoles pharmacology, Pain drug therapy, TRPV Cation Channels antagonists & inhibitors
- Abstract
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.)
- Published
- 2012
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