PharmaCenter Bonn, University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Bonn, Germany.
J Med Chem. 2012 Apr 12;55(7):3331-41. doi: 10.1021/jm300029s. Epub 2012 Mar 27.
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-benzylpiperazine-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.
2-(酰基)氨基-4H-3,1-苯并噻嗪-4-酮和相关的噻吩并噻嗪酮被鉴定为具有新型结构的腺苷受体（AR）拮抗剂。发现 6-甲基-2-苯甲酰氨基-4H-3,1-苯并噻嗪-4-酮（10d）是一种平衡的 AR 拮抗剂，对所有人类（h）亚型具有亲和力（Ki hA(1) 65.6 nM；hA(2A) 120 nM；hA(2B) 360 nM；hA(3) 30.4 nM），而在大鼠（r）中，10d 是一种高选择性 A(1)拮抗剂（rA(1) 7.7 nM；rA(2A) 546 nM；rA(2B) 679 nM，rA(3) >10000 nM）。发现 2-(4-甲基苯甲酰氨基)-4H-3,1-苯并噻嗪-4-酮（10g）是一种有效的人类 A(2A)（68.8 nM）和 A(3)AR 拮抗剂，对其他人类 AR 亚型具有高选择性。与 A(1)和 A(3)AR 不同，A(2A)和 A(2B)AR 可以耐受大体积的 2-酰基取代基。叔丁基（4-氧代-4H-3,1-苯并噻嗪-2-基氨基甲酰）苯甲酰基氨基甲酸酯（15g，Ki hA(2B) 186 nM；hA(2A) 603 nM）和 4-（4-苄基哌嗪-1-羰基）-N-（4-氧代-4H-3,1-苯并噻嗪-2-基）苯甲酰胺（15k，hA(2A) 69.5 nM；hA(2B) 178 nM）对其他 AR 亚型具有高度选择性。2-酰氨基-3,1-苯并噻嗪-4-酮代表了新型的支架，适合开发针对四种受体亚型的每种亚型的强效和选择性 AR 拮抗剂。
