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.
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.
authors: Discovery Research, Cephalon, Incorporated, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. rhudkins@cephalon.com
authors: Robert L
authors: RL
authors: Hudkins
authors: James L
authors: JL
authors: Diebold
authors: Ming
authors: M
authors: Tao
authors: Kurt A
authors: KA
authors: Josef
authors: Chung Ho
authors: CH
authors: Park
authors: Thelma S
authors: TS
authors: Angeles
authors: Lisa D
authors: LD
authors: Aimone
authors: Jean
authors: J
authors: Husten
authors: Mark A
authors: MA
authors: Ator
authors: Sheryl L
authors: SL
authors: Meyer
authors: Beverly P
authors: BP
authors: Holskin
authors: John T
authors: JT
authors: Durkin
authors: Alexander A
authors: AA
authors: Fedorov
authors: Elena V
authors: EV
authors: Fedorov
authors: Steven C
authors: SC
authors: Almo
authors: Joanne R
authors: JR
authors: Mathiasen
authors: Donna
authors: D
authors: Bozyczko-Coyne
authors: Michael S
authors: MS
authors: Saporito
authors: Richard W
authors: RW
authors: Scott
authors: John P
authors: JP
authors: Mallamo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002227:Carbazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D066298:In Vitro Techniques; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D002227:Carbazoles; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C532164:2-isopropoxy-12-(2-hydroxyethyl)-13,14-dihydronaphthol(2,1-a)pyrrolo(3,4-c)carbazole-5-one; C532163:2-methoxy-12-(2-hydroxyethyl)-13,14-dihydronaphthol(2,1-a)pyrrolo(3,4-c)carbazole-5-one; C433243:MAP3K9 protein, human