Potent and Selective PI3Kδ Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687)

and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide

 (AM-1430)

Felix Gonzalez-Lopez de Turiso^*∥, Xiaolin Hao†, Youngsook Shin^*‡, Minna Bui†, Iain D. G. Campuzano‡, Mario Cardozo†, Michelle C. Dunn†, Jason Duquette†, Benjamin Fisher†, Robert S. Foti¶, Kirk Henne§, Xiao He†, Yi-Ling Hu#, Ron C. Kelly⊥, Michael G. Johnson†, Brian S. Lucas†, John McCarter‡, Lawrence R. McGee†, Julio C. Medina†, Daniela Metz#, Tisha San Miguel‡, Deanna Mohn#, Thuy Tran§, Christine Vissinga#, Sharon Wannberg#, Douglas A. Whittington∥, John Whoriskey#, Gang Yu#, Leeanne Zalameda‡, Xuxia Zhang#, and Timothy D. Cushing†

^†Department of Therapeutic Discovery, ^§Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States

^‡Department of Therapeutic Discovery, ^#Department of Inflammation Research, ^⊥Drug Product Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States

^∥Department of Therapeutic Discovery, ^¶Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States

J. Med. Chem., 2016, 59 (15), pp 7252–7267

DOI: 10.1021/acs.jmedchem.6b00827

Publication Date (Web): July 14, 2016

Copyright © 2016 American Chemical Society

*E-mail: felix.gonzalezlopezdeturiso@biogen.com. Phone: 617-914-1295., *E-mail: yshin@amgen.com. Phone: 805-313-2422.

Abstract

 

 

 

 

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00827.

• (i) Biological assays; (ii) enzyme selectivity data of compounds 6a (AM-0687) and 7 (AM-1430); (iii) molecular formula strings and the associated biochemical and biological data; and (iv) crystal structure of PI3Kγ in complex with compound 5g (PDF)
• (CSV)

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  • jm6b00827_si_001.pdf (1.24 MB)

• • jm6b00827_si_002.csv (1.55 kB)

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