Mixed-Lineage Kinase 1 and Mixed-Lineage Kinase 3 Subtype-Selective Dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, Mixed-Lineage Kinase 1 Crystallography, and Oral in Vivo Activit

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• 作者：Robert L. Hudkins ; James L. Diebold ; Ming Tao ; Kurt A. Josef ; Chung Ho Park ; Thelma S. Angeles ; Lisa D. Aimone ; Jean Husten ; Mark A. Ator ; Sheryl L. Meyer ; Beverly P. Holskin ; John T. Durkin ; Alexande
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：September 25, 2008
• 年：2008
• 卷：51
• 期：18
• 页码：5680-5689
• 全文大小：252K
• 年卷期：v.51,no.18(September 25, 2008)
• ISSN：1520-4804

文摘

The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R² and R¹² positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure−activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.