Hit-to-lead optimization of a series of carboxamides of ethyl 2-amino-4-phenylthiazole-5-carboxylates as novel adenosine A2A receptor antagonists.
Herein we describe the discovery of a series of novel adenosine A(2A) receptor antagonists. A successful hit-to-lead optimization of an HTS hit led to replacement of a metabolically labile ester moiety with a heteroaromatic group. A compound from the series, (cyclopropanecarboxylic acid [5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-amide, compound 13), was shown to be effective in reversing haloperidol-induced hypolocomotion, a model of motor dysfunction in Parkinson's Disease.
Sams
Anette Graven
AG
Medicinal Chemistry Research, H. Lundbeck A/S, Valby, Denmark. anette.sams@leo-pharma.com
Mikkelsen
Gitte Kobberøe
GK
Larsen
Mogens
M
Torup
Lars
L
Brennum
Lise Tøttrup
LT
Schrøder
Tenna Juul
TJ
Bang-Andersen
Benny
B
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D043705:Receptor, Adenosine A2A / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000577:Amides; D002264:Carboxylic Acids; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A