Benzothiazinones: A Novel Class of Adenosine Receptor Antagonists Structurally Unrelated to Xanthine and Adenine Derivatives

2-(Acyl)amino-4H-3,1-benzothiazin-4-ones and related thienothiazinones were identified as structurally novel antagonists at adenosine receptors (ARs). 6-Methyl-2-benzoylamino-4H-3,1-benzothiazin-4-one (10d) was found to be a balanced AR antagonist with affinity for all human (h) subtypes (K-i hA(1) 65.6 nM; hA(2A) 120 nM; hA(2B) 360 nM; hA(3) 30.4 nM), while in rat (r), 10d was a highly potent A(1)-selective antagonist (rA(1) 7.7 nM; rA(2A) 546 nM; rA(2B) 679 nM, rA(3) >10000 nM). 2-(4-Methylbenzoylamino)-4H-3,1-benzothiazin-4-one (10g) was found to be a potent antagonist at human A(2A) (68.8 nM) and A(3) ARs (23.0 nM) with high selectivity versus the other human AR subtypes. In contrast to A(1) and A(3) ARs, A(2A) and A(2B) ARs tolerated bulky 2-acyl substituents. tert-Butyl (4-oxo-4H-3,1-benzothiazin-2-ylcarbamoyl)benzylcarbamate (15g, K-i hA(2B) 186 nM; hA(2A) 603 nM) and 4-(4-benz-ylpiperazine-1-carbonyl)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)benzamide (15k, hA(2A) 69.5 nM; hA(2B) 178 nM) were highly selective versus the other AR subtypes. 2-Acylamino-3,1-benzothiazin-4-ones represent novel scaffolds suitable for the development of potent and selective AR antagonists for each of the four receptor subtypes.