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1. 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 activity in 1-methyl-4-phenyltetrahydropyridine models.

Author

Hudkins RL, Diebold JL, Tao M, Josef KA, Park CH, Angeles TS, Aimone LD, Husten J, Ator MA, Meyer SL, Holskin BP, Durkin JT, Fedorov AA, Fedorov EV, Almo SC, Mathiasen JR, Bozyczko-Coyne D, Saporito MS, Scott RW, and Mallamo JP

Subjects
Administration, Oral, Animals, Carbazoles administration & dosage, Carbazoles chemistry, Cell Line, Tumor, Crystallography, X-Ray, Humans, In Vitro Techniques, Magnetic Resonance Spectroscopy, Mice, Molecular Structure, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Pyrrolidinones administration & dosage, Pyrrolidinones chemistry, Rats, Mitogen-Activated Protein Kinase Kinase Kinase 11, Carbazoles pharmacology, MAP Kinase Kinase Kinases antagonists & inhibitors, Models, Molecular, Protein Kinase Inhibitors pharmacology, Pyrrolidinones pharmacology
Abstract

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 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.

Published
2008
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