Discovery and in Vivo Evaluation of the 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)

• Published in: Journal of medicinal chemistry 2016-08, Vol.59 (15), p.7252-7267
• Main Authors: Gonzalez-Lopez de Turiso, Felix, Hao, Xiaolin, Shin, Youngsook, Bui, Minna, Campuzano, Iain D. G, Cardozo, Mario, Dunn, Michelle C, Duquette, Jason, Fisher, Benjamin, Foti, Robert S, Henne, Kirk, He, Xiao, Hu, Yi-Ling, Kelly, Ron C, Johnson, Michael G, Lucas, Brian S, McCarter, John, McGee, Lawrence R, Medina, Julio C, Metz, Daniela, San Miguel, Tisha, Mohn, Deanna, Tran, Thuy, Vissinga, Christine, Wannberg, Sharon, Whittington, Douglas A, Whoriskey, John, Yu, Gang, Zalameda, Leeanne, Zhang, Xuxia, Cushing, Timothy D
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Humans; Mice; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00827

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.