期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 51, 期 18, 页码 5680-5689出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm8005838
关键词
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The optimization of the dihydronaphthyl[3,4-a] pyrrolo [3,4-c] carbazole-5-one R(2) and R(12) 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 MLK I 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.
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