Journal article
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, v 51(18), pp 5680-5689
25 Sep 2008
PMID: 18714982
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 MLK I 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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Details
- Title
- 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
- Creators
- Robert L. Hudkins - Albert Einstein College of MedicineJames L. Diebold - Albert Einstein College of MedicineMing Tao - Albert Einstein College of MedicineKurt A. Josef - Albert Einstein College of MedicineChung Ho Park - Albert Einstein College of MedicineThelma S. Angeles - Albert Einstein College of MedicineLisa D. Aimone - Albert Einstein College of MedicineJean Husten - Albert Einstein College of MedicineMark A. Ator - Albert Einstein College of MedicineSheryl L. Meyer - Albert Einstein College of MedicineBeverly P. Holskin - Albert Einstein College of MedicineJohn T. Durkin - Albert Einstein College of MedicineAlexander A. Fedorov - Albert Einstein College of MedicineElena V. Fedorov - Albert Einstein College of MedicineSteven C. Almo - Albert Einstein College of MedicineJoanne R. Mathiasen - Albert Einstein College of MedicineDonna Bozyczko-Coyne - Cephalon Inc, Discovery Res, W Chester, PA 19380 USAMichael S. Saporito - Albert Einstein College of MedicineRichard W. Scott - Albert Einstein College of MedicineJohn P. Mallamo - Albert Einstein College of Medicine
- Publication Details
- Journal of medicinal chemistry, v 51(18), pp 5680-5689
- Publisher
- Amer Chemical Soc
- Number of pages
- 10
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000259342700021
- Scopus ID
- 2-s2.0-52449127474
- Other Identifier
- 991021900193304721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal