| Literature DB >> 27411843 |
Felix Gonzalez-Lopez de Turiso1,2,3, Xiaolin Hao1,2,3, Youngsook Shin1,2,3, Minna Bui1,2,3, Iain D G Campuzano1,2,3, Mario Cardozo1,2,3, Michelle C Dunn1,2,3, Jason Duquette1,2,3, Benjamin Fisher1,2,3, Robert S Foti1,2,3, Kirk Henne1,2,3, Xiao He1,2,3, Yi-Ling Hu1,2,3, Ron C Kelly1,2,3, Michael G Johnson1,2,3, Brian S Lucas1,2,3, John McCarter1,2,3, Lawrence R McGee1,2,3, Julio C Medina1,2,3, Daniela Metz1,2,3, Tisha San Miguel1,2,3, Deanna Mohn1,2,3, Thuy Tran1,2,3, Christine Vissinga1,2,3, Sharon Wannberg1,2,3, Douglas A Whittington1,2,3, John Whoriskey1,2,3, Gang Yu1,2,3, Leeanne Zalameda1,2,3, Xuxia Zhang1,2,3, Timothy D Cushing1,2,3.
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.Entities:
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Year: 2016 PMID： 27411843 DOI： 10.1021/acs.jmedchem.6b00827
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446