Discovery of a novel series of pyridine and pyrimidine carboxamides as potent and selective covalent inhibitors of Btk

被引：13

作者：

Caldwell, Richard ^{[1
]}

Liu-Bujalski, Lesley ^{[1
]}

Qiu, Hui ^{[1
]}

Mochalkin, Igor ^{[1
]}

Jones, Reinaldo ^{[1
]}

Neagu, Constantin ^{[1
]}

Goutopoulos, Andreas ^{[1
]}

Grenningloh, Roland ^{[1
]}

Johnson, Theresa ^{[1
]}

Sherer, Brian ^{[1
]}

Gardberg, Anna ^{[2
]}

Follis, Ariele Viacava ^{[1
]}

Morandi, Federica ^{[3
]}

Head, Jared ^{[1
]}

机构：

[1] EMD Serono Res & Dev Inst Inc, 45A Middlesex Turnpike, Billerica, MA 01821 USA

[2] Constellat Pharmaceut, 215 First St,Suite 200, Cambridge, MA 02142 USA

[3] L Hoffmann La Roche AG, Konzern Hauptsitz, Grenzacherstr 124, CH-4070 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 21期

关键词：

Covalent; Irreversible; Btk inhibitor; Fragment; BRUTONS TYROSINE KINASE; MANTLE-CELL LYMPHOMA; B-CELL; TARGETING BTK; IBRUTINIB; LEUKEMIA; INCREASES; GENE;

D O I：

10.1016/j.bmcl.2018.09.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity.

引用

页码：3419 / 3424

页数：6

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