Hammond Marlys, Washburn David G, Hoang H Tram, Manns Sharada, Frazee James S, Nakamura Hiroko, Patterson Jaclyn R, Trizna Walter, Wu Charlene, Azzarano Leonard M, Nagilla Rakesh, Nord Melanie, Trejo Rebecca, Head Martha S, Zhao Baoguang, Smallwood Angela M, Hightower Kendra, Laping Nicholas J, Schnackenberg Christine G, Thompson Scott K
Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Bioorg Med Chem Lett. 2009 Aug 1;19(15):4441-5. doi: 10.1016/j.bmcl.2009.05.051. Epub 2009 May 18.
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.
先导血清和糖皮质激素相关激酶1（SGK1）抑制剂4-（5-苯基-1H-吡咯并[2,3-b]吡啶-3-基）苯甲酸（1）和{4-[5-（2-萘基）-1H-吡咯并[2,3-b]吡啶-3-基]苯基}乙酸（2）在大鼠体内的药物清除率（DNAUC）值较低，部分原因是葡萄糖醛酸共轭物的形成和排泄。这些药代动力学/葡萄糖醛酸化问题通过在1的关键羧酸盐官能团的邻位3-苯环上引入取代基或在2的羧酸盐和苯环之间的基团上进行取代来解决。已鉴定出其中三种类似物具有良好的SGK1抑制效力，并且具有适合体内测试的药物清除率值。
