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 Chemistry
Robert L HudkinsJohn 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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Citations

Oct 31, 2009·Nature Reviews. Drug Discovery·Laura K ChicoD Martin Watterson
Dec 4, 2009·Human Molecular Genetics·Sérgia VelhoRaquel Seruca
Nov 2, 2013·Future Medicinal Chemistry·Dana FerrarisDerek Welsbie
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Aug 21, 2014·The Journal of Organic Chemistry·Amy A van LoonErin T Pelkey
Jun 5, 2018·Journal of Medicinal Chemistry·Michael SiuJoseph W Lewcock

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