NYCOMED GmbH, Departments of Medicinal Chemistry, Biochemistry, Pharmacology, and Physicochemistry, Byk-Gulden-Strasse 2, D-78467 Konstanz, Germany.
J Med Chem. 2010 May 13;53(9):3645-74. doi: 10.1021/jm100040c.
Potassium-competitive acid blockers (P-CABs) constitute a new therapeutic option for the treatment of acid-related diseases that are widespread and constitute a significant economical burden. Enantiomerically pure tetrahydrochromenoimidazoles were prepared using the readily available candidate 4 (BYK 405879) as starting material or the Noyori asymmetric reduction of ketones as key reaction. A comprehensive SAR regarding the influence of the 5-carboxamide and the 8-aryl residue on in vitro activity, acid-suppression in the Ghosh Schild rat, and affinity toward the hERG channel was established. In addition, efficacy and duration of the antisecretory action was examined for the most promising target compounds by 24 h pH-metry in the fistula dog and a significantly different SAR was observed as compared to the Ghosh Schild rat. Several tetrahydrochromenoimidazoles were identified that possessed a comparable profile as the candidate 4.
钾竞争性酸阻滞剂（P-CABs）为治疗广泛存在且具有重大经济负担的酸相关疾病提供了一种新的治疗选择。使用易得的候选物 4（BYK 405879）作为起始原料或诺里不对称酮还原作为关键反应，制备了对映体纯的四氢色烯咪唑。对 5-羧酰胺和 8-芳基残基对体外活性、Ghosh Schild 大鼠中的抑酸作用以及对 hERG 通道的亲和力的影响进行了全面的 SAR 研究。此外，通过瘘管狗 24 小时 pH 测定法对最有前途的靶化合物的抗分泌作用的疗效和持续时间进行了研究，与 Ghosh Schild 大鼠相比，观察到了显著不同的 SAR。鉴定出几种四氢色烯咪唑，它们具有与候选物 4 相当的特性。
