Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors

  • J Med Chem. 2018 Jun 28;61(12):5435-5441. doi: 10.1021/acs.jmedchem.8b00447.
Nils Pemberton ,  Mickael Mogemark ,  Susanne Arlbrandt ,  Peter Bold ,  Rhona J Cox ,  Cristina Gardelli ,  Neil S Holden ,  Kostas Karabelas ,  Johan Karlsson ,  Sarah Lever ,  Xueshan Li  1 ,  Helena Lindmark ,  Monica Norberg ,  Matthew W D Perry ,  Jens Petersen ,  Sandra Rodrigo Blomqvist ,  Matthew Thomas ,  Christian Tyrchan ,  Annika Westin Eriksson ,  Pavol Zlatoidsky ,  Linda Öster
Affiliations
  • 1. Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA , Beijing 100176 , P. R. China.
PMID: 29852070 DOI: 10.1021/acs.jmedchem.8b00447
Abstract

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ Inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

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