title: Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.
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.
authors.affiliation: AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden.
authors.forename: Yevgeni
authors.initials: Y
authors.lastname: Besidski
authors.forename: William
authors.initials: W
authors.lastname: Brown
authors.forename: Johan
authors.initials: J
authors.lastname: Bylund
authors.forename: Michael
authors.initials: M
authors.lastname: Dabrowski
authors.forename: Sophie
authors.initials: S
authors.lastname: Dautrey
authors.forename: Magali
authors.initials: M
authors.lastname: Harter
authors.forename: Lucy
authors.initials: L
authors.lastname: Horoszok
authors.forename: Yin
authors.initials: Y
authors.lastname: Hu
authors.forename: Dean
authors.initials: D
authors.lastname: Johnson
authors.forename: Shawn
authors.initials: S
authors.lastname: Johnstone
authors.forename: Paul
authors.initials: P
authors.lastname: Jones
authors.forename: Sandrine
authors.initials: S
authors.lastname: Leclerc
authors.forename: Karin
authors.initials: K
authors.lastname: Kolmodin
authors.forename: Inger
authors.initials: I
authors.lastname: Kers
authors.forename: Maryse
authors.initials: M
authors.lastname: Labarre
authors.forename: Denis
authors.initials: D
authors.lastname: Labrecque
authors.forename: Jennifer
authors.initials: J
authors.lastname: Laird
authors.forename: Therese
authors.initials: T
authors.lastname: Lundström
authors.forename: John
authors.initials: J
authors.lastname: Martino
authors.forename: Mickaël
authors.initials: M
authors.lastname: Maudet
authors.forename: Alexander
authors.initials: A
authors.lastname: Munro
authors.forename: Martin
authors.initials: M
authors.lastname: Nylöf
authors.forename: Andrea
authors.initials: A
authors.lastname: Penwell
authors.forename: Didier
authors.initials: D
authors.lastname: Rotticci
authors.forename: Andis
authors.initials: A
authors.lastname: Slaitas
authors.forename: Anna
authors.initials: A
authors.lastname: Sundgren-Andersson
authors.forename: Mats
authors.initials: M
authors.lastname: Svensson
authors.forename: Gitte
authors.initials: G
authors.lastname: Terp
authors.forename: Huascar
authors.initials: H
authors.lastname: Villanueva
authors.forename: Christopher
authors.initials: C
authors.lastname: Walpole
authors.forename: Ronald
authors.initials: R
authors.lastname: Zemribo
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Griffin
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012995:Solubility; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D052160:Benzothiazoles; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C005465:benzothiazole