2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor.
The inhibition of PKC-zeta has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-zeta). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH(2) derivative. The analog displays good selectivity over other PKC isoforms (alpha, betaII, gamma, delta, epsilon, mu, theta, eta and iota/lambda) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).
Trujillo
John I
JI
Department of Medicinal Chemistry, Pfizer Global Research and Development, 700 Chesterfield Pkwy, AA236, Chesterfield, MO 63017, USA. john.i.trujillo@pfizer.com
Kiefer
James R
JR
Huang
Wei
W
Thorarensen
Atli
A
Xing
Li
L
Caspers
Nicole L
NL
Day
Jacqueline E
JE
Mathis
Karl J
KJ
Kretzmer
Kuniko K
KK
Reitz
Beverley A
BA
Weinberg
Robin A
RA
Stegeman
Roderick A
RA
Wrightstone
Ann
A
Christine
Lori
L
Compton
Robert
R
Li
Xiong
X
D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000737:chemistry* / Q000302:isolation & purification*; D000099221:Protein Kinase C zeta
D001562:Benzimidazoles; D019925:Cyclin A; D051357:Cyclin-Dependent Kinase 2; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020033:Protein Isoforms; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta; C031000:benzimidazole