Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

Gui-Dong Zhu,*† Viraj B. Gandhi,† Jianchun Gong,† Sheela Thomas,† Keith W. Woods,† Xiaohong Song,† Tongmei Li,† R. Bruce Diebold,† Yan Luo,† Xuesong Liu,† Ran Guan,† Vered Klinghofer,† Eric F. Johnson,† Jennifer Bouska,† Amanda Olson,† Kennan C. Marsh,‡ Vincent S. Stoll,§ Mulugeta Mamo,§ James Polakowski, Thomas J. Campbell, Ruth L. Martin, Gary A. Gintant, Thomas D. Penning,† Qun Li,† Saul H. Rosenberg,† and Vincent L. Giranda†
Cancer Research, Preclinical Safety, Structural Biology, Integrative Pharmacology, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6101
J. Med. Chem., 2007, 50 (13), pp 2990–3003
DOI: 10.1021/jm0701019
Publication Date (Web): May 25, 2007
Copyright © 2007 American Chemical Society
*

 To whom correspondence should be addressed. Phone:  847-935-1305. Fax:  847-935-5165. E-mail:  gui-dong.zhu@abbott.com.

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†

 Cancer Research.

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 Preclinical Safety.

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 Structural Biology.

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 Integrative Pharmacology.

Abstract

Abstract Image

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.

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  • Published In Issue June 28, 2007
  • Received January 25, 2007

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