Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases

被引：23

作者：

Erra, Montse ^{[1
]}

Taltavull, Joan ^{[1
]}

Greco, Angelique ^{[1
,5
]}

Javier Bernal, Francisco ^{[1
]}

Francisco Caturla, Juan ^{[1
]}

Gracia, Jordi ^{[1
]}

Dominguez, Maria ^{[2
]}

Sabate, Mar ^{[2
]}

Paris, Stephane ^{[1
]}

Soria, Salome ^{[1
]}

Hernandez, Begona ^{[1
,7
]}

Armengol, Clara

Cabedo, Judit ^{[3
,4
]}

Bravo, Monica ^{[4
]}

Calama, Elena ^{[4
]}

Miralpeix, Montserrat ^{[4
]}

Lehner, Martin D. ^{[4
,6
]}

机构：

[1] Almirall R&D, Med Chem & Screening, Barcelona 08980, Spain

[2] Almirall R&D, Pharmacokinet & Metab, Barcelona 08980, Spain

[3] Almirall R&D, Syst Biol, Barcelona 08980, Spain

[4] Almirall R&D, Resp Therapeut Area, Barcelona 08980, Spain

[5] Pharmaxis Ltd, 20 Rodborough Rd, Frenchs Forest, NSW 2086, Australia

[6] Bionor SE, Kerschensteinerstr 11-15, D-92318 Neumarkt, Germany

[7] Fundacio ACE, Marques Sentmenat,57, Barcelona 08029, Spain

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 01期

关键词：

Phosphoinositide-3-kinase delta inhibitor; PI3K delta inhibitor; structure-activity relationship; autoimmune diseases; inflammatory diseases; lead optimization; PHOSPHOINOSITIDE 3-KINASE DELTA; IMMUNE-RESPONSES; P110-DELTA; IDELALISIB; AUTOIMMUNE; BINDING; MICE;

D O I：

10.1021/acsmedchemlett.6b00438

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The delta isoform of the phosphatidylinositol 3-kinase (PI3K delta) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3K delta inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure activity relationships and structure property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.

引用

页码：118 / 123

页数：6

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