title: New highly potent and selective adenosine A(3) receptor antagonists.
abstract: A class of potent, selective adenosine A(3) receptor antagonists was obtained via optimisation of the screening hit N-[4-(4-methoxyphenyl)-thiazol-2-yl]-acetamide. Structural modifications of this hit revealed very quickly that a 5-(pyridin-4-yl) substituent on the 2-aminothiazole ring was optimal for high potency at the adenosine A(3) receptor. Structure activity relationship studies led to both potent and selective A(3) receptor antagonists, including N-[5-pyridin-4-yl-4-(3,4,5-trimethoxyphenyl)-thiazol-2-yl]-acetamide, a highly potent aden-osine A(3) receptor antagonist with greater than 100- fold selectivity against the related adenosine receptors. As well as demonstrating selective in vitro binding on the human A(3) adenosine receptor, this compound was also shown to selectively block the rat A(3) receptor in vivo. This important new compound can be readily synthesised in four steps from commercially available starting materials.
authors.affiliation: Respiratory Disease Area, Novartis Horsham Research Center, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK. neil.press@pharma.novartis.com
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Press
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Pamela
authors.initials: P
authors.lastname: Tranter
authors.forename: David
authors.initials: D
authors.lastname: Beer
authors.forename: Ken
authors.initials: K
authors.lastname: Jones
authors.forename: Alexander
authors.initials: A
authors.lastname: Faessler
authors.forename: Richard
authors.initials: R
authors.lastname: Heng
authors.forename: Christine
authors.initials: C
authors.lastname: Lewis
authors.forename: Trevor
authors.initials: T
authors.lastname: Howe
authors.forename: Peter
authors.initials: P
authors.lastname: Gedeck
authors.forename: Lazzaro
authors.initials: L
authors.lastname: Mazzoni
authors.forename: John R
authors.initials: JR
authors.lastname: Fozard
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D015195:Drug Design; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000081:Acetamides; D058918:Adenosine A3 Receptor Antagonists; D013844:Thiazoles