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
journal contributionposted on 25.09.2008, 00:00 by 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, Alexander A. Fedorov, Elena V. Fedorov, Steven C. Almo, Joanne R. Mathiasen, Donna Bozyczko-Coyne, Michael S. Saporito, Richard W. Scott, John P. Mallamo
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.