浮米每周文献快讯：2015年01月(三)

浮米每周文献快讯：2015年01月(三) 作者：浮米网 来源：浮米网  2015-01-19

1. 原文标题及出处：

Discovery and Preclinical Profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a Highly Potent, Selective, Brain Penetrant, and in Vivo Active LRRK2 Kinase Inhibitor

J. Med. Chem., 2015, 58 (1), pp 419–432

DOI: 10.1021/jm5014055

公司/组织：Pfizer

候选药物化学结构式/活性：

                               
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靶点/作用机制：富亮氨酸重复受体激酶2(LRRK2)抑制剂

摘要原文：

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson’s disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.

备注：

LRRK2是治疗帕金森病的潜在靶点。

2. 原文标题及出处：

Tetra-Substituted Pyridinylimidazoles As Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase 3 for Potential Treatment of Neurodegenerative Diseases

J. Med. Chem., 2015, 58 (1), pp 443–456

DOI: 10.1021/jm501557a

公司/组织：诺华

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靶点/作用机制：p38αMAPK & JNK3双靶点抑制剂

摘要原文：

Tetra-substituted imidazoles were designed as dual inhibitors of c-Jun N-terminal kinase (JNK) 3 and p38α mitogen-activated protein (MAP) kinase. A library of 45 derivatives was prepared and evaluated in a kinase activity assay for their ability to inhibit both kinases, JNK3 and p38α MAP kinase. Dual inhibitors with IC50 values down to the low double-digit nanomolar range at both enzymes were identified. The best balanced dual JNK3/p38α MAP kinase inhibitors are 6m (IC50: JNK3, 18 nM; p38α, 30 nM) and 14d (IC50: JNK3, 26 nM; p38α, 34 nM) featuring both excellent solubility and metabolic stability. They may serve as useful tool compounds for preclinical proof-of-principle studies in order to validate the synergistic role of both kinases in the progression of Huntington’s disease.

备注：

                               
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3. 原文标题及出处：

Discovery and in Vivo Evaluation of (S)-N-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

J. Med. Chem., 2015, 58 (1), pp 480–511

DOI: 10.1021/jm501624r

公司/组织：Amgen

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靶点/作用机制：PI3Kδ抑制剂

摘要原文：

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

备注：

PI3Kδ作为自身免疫性疾病以及慢性非自身免疫疾病如COPD的治疗靶点。

4. 原文标题及出处：

Structure-Based Drug Design of RN486, a Potent and Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis

J. Med. Chem., 2015, 58 (1), pp 512–516

DOI: 10.1021/jm500305p

公司/组织：Roche

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靶点/作用机制：BTK抑制剂

摘要原文：

Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012, 341, 90), which was selected for advanced preclinical characterization based on its favorable properties.

备注：

BTK作为SYK下游激酶，也在B细胞和肥大细胞的激活中发挥着重要作用，与风湿性关节炎相关。

(by 浮米网)

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感谢楼主分享。

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