2. Academic Validation
  3. 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

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

  • J Med Chem. 2008 Sep 25;51(18):5680-9. doi: 10.1021/jm8005838.
Robert L Hudkins 1,  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
Affiliations

Affiliation

  • 1 Discovery Research, Cephalon, Incorporated, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. rhudkins@cephalon.com
PMID: 18714982 DOI: 10.1021/jm8005838
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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