title: The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore.
abstract: Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease.
authors.affiliation: Department of Chemistry, Heart Failure Disease Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, United States.
authors.forename: David G
authors.initials: DG
authors.lastname: Washburn
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Holt
authors.forename: Jason
authors.initials: J
authors.lastname: Dodson
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: McAtee
authors.forename: Lamont R
authors.initials: LR
authors.lastname: Terrell
authors.forename: Linda
authors.initials: L
authors.lastname: Barton
authors.forename: Sharada
authors.initials: S
authors.lastname: Manns
authors.forename: Anna
authors.initials: A
authors.lastname: Waszkiewicz
authors.forename: Christina
authors.initials: C
authors.lastname: Pritchard
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Gillie
authors.forename: Dwight M
authors.initials: DM
authors.lastname: Morrow
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Davenport
authors.forename: Irina M
authors.initials: IM
authors.lastname: Lozinskaya
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Guss
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Basilla
authors.forename: Lorena Kallal
authors.initials: LK
authors.lastname: Negron
authors.forename: Michael
authors.initials: M
authors.lastname: Klein
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
authors.forename: Rusty E
authors.initials: RE
authors.lastname: Fries
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Jensen
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xu
authors.forename: Christine G
authors.initials: CG
authors.lastname: Schnackenberg
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology*; D004075:Diglycerides / Q000378:metabolism; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D004075:Diglycerides; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D013844:Thiazoles; C038237:1-oleoyl-2-acetylglycerol
keywords: 1-Oleoyl-2-acetyl-glycerol; Anilino-thiazole; Canonical transient receptor potential channel; OAG; TRPC3; TRPC6