Linked Life Data

18714982

Source:http://linkedlifedata.com/resource/pubmed/id/18714982

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pubmed-article:18714982pubmed:abstractTextThe 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.lld:pubmed
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pubmed-article:18714982pubmed:articleTitleMixed-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.lld:pubmed
pubmed-article:18714982pubmed:affiliationDiscovery Research, Cephalon, Incorporated, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. rhudkins@cephalon.comlld:pubmed
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