title: N-1-Alkyl-2-oxo-2-aryl amides as novel antagonists of the TRPA1 receptor.
abstract: A series of potent antagonists of the ion channel transient receptor potential A1 (TRPA1) was developed by modifying lead structure 16 that was discovered by high-throughput screening. Based on lead compound 16, a SAR was established, showing a narrow region at the nitro-aromatic R(1) moiety and at the warhead, while the R(2) side had a much wider scope including ureas and carbamates. Compound 16 inhibits Ca(2+)-activated TRPA1 currents reversibly in whole cell patch clamp experiments, indicating that under in vivo conditions, it does not react covalently, despite its potentially electrophilic ketone.
authors.affiliation: Medicinal Chemistry, CNSP iMed, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden. karl_sa.vallin@bredband.net
authors.forename: Karl S A
authors.initials: KS
authors.lastname: Vallin
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Sterky
authors.forename: Eva
authors.initials: E
authors.lastname: Nyman
authors.forename: Jenny
authors.initials: J
authors.lastname: Bernström
authors.forename: Rebecka
authors.initials: R
authors.lastname: From
authors.forename: Christian
authors.initials: C
authors.lastname: Linde
authors.forename: Alexander B E
authors.initials: AB
authors.lastname: Minidis
authors.forename: Andreas
authors.initials: A
authors.lastname: Nolting
authors.forename: Katja
authors.initials: K
authors.lastname: Närhi
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Santangelo
authors.forename: Fernando W
authors.initials: FW
authors.lastname: Sehgelmeble
authors.forename: Daniel
authors.initials: D
authors.lastname: Sohn
authors.forename: Jennie
authors.initials: J
authors.lastname: Strindlund
authors.forename: Dirk
authors.initials: D
authors.lastname: Weigelt
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014508:Urea / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D015220:Calcium Channels; D002219:Carbamates; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; D014508:Urea; D002118:Calcium