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.
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.
Hudkins
Robert L
RL
Discovery Research, Cephalon, Incorporated, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. rhudkins@cephalon.com
Diebold
James L
JL
Tao
Ming
M
Josef
Kurt A
KA
Park
Chung Ho
CH
Angeles
Thelma S
TS
Aimone
Lisa D
LD
Husten
Jean
J
Ator
Mark A
MA
Meyer
Sheryl L
SL
Holskin
Beverly P
BP
Durkin
John T
JT
Fedorov
Alexander A
AA
Fedorov
Elena V
EV
Almo
Steven C
SC
Mathiasen
Joanne R
JR
Bozyczko-Coyne
Donna
D
Saporito
Michael S
MS
Scott
Richard W
RW
Mallamo
John P
JP
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
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