2uzw: Difference between revisions
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==Overview== | ==Overview== | ||
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. ... | 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 Structure== | ==About this Structure== | ||
2UZW is a | 2UZW is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with SS4 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/cAMP-dependent_protein_kinase cAMP-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.11 2.7.11.11] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2UZW OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 13:09:56 2007'' | ||
