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The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R 2and R 12positions 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 14and 16were 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. [ABSTRACT FROM AUTHOR]

Structural modification of the indolecarbazole natural product ()K-252a identified structural requirements for MLK activity and a novel series of potent fused pyrrolocarbazole MLK1/3 inhibitors. The SAR revealed that the lactam regiochemistry, the shape of the heterocycle, and aryl rings B and F are important to MLK activity. Heteroatom and alkyl replacement of the N-12 and/or N-13 indole nitrogen atoms identified the nonplanar dihydronaphthyl3,4-apyrrolo3,4-ccarbazole-7-one (8) and corresponding 5,7-dione (7) as potent cell-permeable MLK1/3 family-selective leads with in vitro activity comparable to that of ()K-252a and determined them to be 2- to 3-fold more potent than the aglycone natural product K-252c. [ABSTRACT FROM AUTHOR]