Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration.

Autor:	Perry MWD; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Björhall K; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Bonn B; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Carlsson J, Chen Y; Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA, Beijing 100176, P.R. China., Eriksson A; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Fredlund L, Hao H; Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA, Beijing 100176, P.R. China., Holden NS; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Karabelas K; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Lindmark H, Liu F; Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA, Beijing 100176, P.R. China., Pemberton N; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Petersen J, Rodrigo Blomqvist S; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Smith RW; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Svensson T; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Terstiege I; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Tyrchan C; Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca Gothenburg , Pepparedsleden 1, SE-431 83 Mölndal, Sweden., Yang W; Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA, Beijing 100176, P.R. China., Zhao S; Pharmaron Beijing Co., Ltd. , No. 6 Taihe Road, BDA, Beijing 100176, P.R. China., Öster L
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2017 Jun 22; Vol. 60 (12), pp. 5057-5071. Date of Electronic Publication: 2017 Jun 07.
DOI:	10.1021/acs.jmedchem.7b00401
Abstrakt:	PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC 50 > 9), and by careful manipulation of the pK a and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated.
Databáze:	MEDLINE
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