2-苯磺酰基-8a-苄基-六氢-2H-异喹啉-6-酮作为选择性糖皮质激素受体拮抗剂。
2-Benzenesulfonyl-8a-benzyl-hexahydro-2H-isoquinolin-6-ones as selective glucocorticoid receptor antagonists.
作者信息
Clark Robin D, Ray Nicholas C, Blaney Paul, Crackett Peter H, Hurley Christopher, Williams Karen, Dyke Hazel J, Clark David E, Lockey Peter M, Devos Rene, Wong Melanie, White Anne, Belanoff Joseph K
机构信息
Corcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA.
出版信息
Bioorg Med Chem Lett. 2007 Oct 15;17(20):5704-8. doi: 10.1016/j.bmcl.2007.07.055. Epub 2007 Aug 19.
The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay. These compounds were devoid of affinity for other steroidal receptors (ER, AR, MR, and PR). Analogues based on an alternative putative binding mode (CP-like) were found to be inactive.
对2-氮杂萘满环系统作为制备糖皮质激素受体（GR）拮抗剂的骨架进行了评估。基于与甾体GR拮抗剂RU-43044相关的假设结合模式，发现了高亲和力、选择性的GR拮抗剂。以（R）-37为例的2-苯磺酰基取代的8a-苄基-六氢-2H-异喹啉-6-酮对GR具有低纳摩尔亲和力，在报告基因测定中具有中等功能活性（200 nM）。这些化合物对其他甾体受体（雌激素受体、雄激素受体、盐皮质激素受体和孕激素受体）没有亲和力。发现基于另一种假定结合模式（CP样）的类似物无活性。
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