Hit-to-lead optimization of a series of carboxamides of ethyl 2-amino-4-phenylthiazole-5-carboxylates as novel adenosine A(2A) receptor antagonists.
Bioorganic & medicinal chemistry letters 2010 Jul 24; In press
Sams A AG, Mikkelsen G GK, Larsen M, Torup L, Brennum L LT, Schrøder T TJ, Bang-Andersen B
Medicinal Chemistry Research, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
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.