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 of Medicinal Chemistry2008Vol. 51(18), pp. 5680–5689
Citations Over TimeTop 22% of 2008 papers
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, А.А. Федоров, E.V. Fedorov, Steven C. Almo, Joanne R. Mathiasen, Donna Bozyczko‐Coyne, Michael S. Saporito, Richard Scott, John P. Mallamo
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.
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