2uzu
PKA STRUCTURES OF INDAZOLE-PYRIDINE SERIES OF AKT INHIBITORS
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OverviewOverview
Compound 7 was identified as a potent (IC50 = 14 nM), selective, and, orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt., While promising efficacy was observed in vivo, this compound showed, effects on depolarization of Purkinje fibers in an in vitro assay and CV, hypotension in vivo. Guided by an X-ray structure of 7 bound to protein, kinase A, which has 80% homology with Akt in the kinase domain, our, efforts have focused on structure-activity relationship (SAR) studies of, the phenyl moiety, in an attempt to address the cardiovascular liability, and further improve the Akt potency. A novel and efficient synthetic route, toward diversely substituted phenyl derivatives of 7 was developed, utilizing a copper-mediated aziridine ring-opening reaction as the key, step. To improve the selectivity of these Akt inhibitors over other, protein kinases, a nitrogen atom was incorporated into selected phenyl, analogues of 7 at the C-6 position of the methyl indazole scaffold. These, modifications resulted in the discovery of inhibitor 37c with greater, potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular, safety profile. The SARs, pharmacokinetic profile, and CV safety of, selected Akt inhibitors will be discussed.
About this StructureAbout this Structure
2UZU is a Protein complex structure of sequences from Bos taurus with as ligand. Active as cAMP-dependent protein kinase, with EC number 2.7.11.11 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase b/akt inhibitors with reduced hypotension., Zhu GD, Gandhi VB, Gong J, Thomas S, Woods KW, Song X, Li T, Diebold RB, Luo Y, Liu X, Guan R, Klinghofer V, Johnson EF, Bouska J, Olson A, Marsh KC, Stoll VS, Mamo M, Polakowski J, Campbell TJ, Martin RL, Gintant GA, Penning TD, Li Q, Rosenberg SH, Giranda VL, J Med Chem. 2007 Jun 28;50(13):2990-3003. Epub 2007 May 25. PMID:17523610
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