浮米每周文献快讯：2014年10月（二）

• 浮米每周文献快讯：2014年10月（二）行业   
•     作者：浮米网 来源：浮米网  2014-10-20
  

1. Bioavailable pyrrolo-benzo-1,4-diazines as Nav1.7 sodium channel blockers for the treatment of pain

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4958–4962

DOI: 10.1016/j.bmcl.2014.09.038

公司/组织：默克

候选药物化学结构式/活性：

                               
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靶点/作用机制：钠离子通道阻断剂

摘要原文：

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure–activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Nav1.7 inhibitory activity and moderate selectivity over Nav1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 μM.

备注：

Nav1.7 作为治疗疼痛的潜在有效靶点。

2. Scaffold hopping towards potent and selective JAK3 inhibitors: Discovery of novel C-5 substituted pyrrolopyrazines

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4969–4975

DOI: 10.1016/j.bmcl.2014.09.031

公司/组织：罗氏

候选药物化学结构式/活性：

                               
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靶点/作用机制：JAK3抑制剂

摘要原文：

The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.

备注：

JAK/STAT通路在细胞因子通路中具有重要作用，靶向JAK激酶有望于治疗包括风湿性关节炎、骨质增生以及癌症等疾病。

                               
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3. Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4984–4988

DOI: 10.1016/j.bmcl.2014.09.030

公司/组织：Boehringer Ingelheim

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靶点/作用机制：抗HCV

摘要原文：

Previous investigations identified 2′-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin.

备注：

一些代表性的抗HCV药物

                               
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4. Discovery of tetrahydroisoquinoline-based bivalent heterodimeric IAP antagonists

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5022–5029

DOI: 10.1016/j.bmcl.2014.09.022

公司/组织：Bristol-Myers Squibb

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靶点/作用机制：IAP（凋亡蛋白抑制剂）拮抗剂

摘要原文：

Bivalent heterodimeric IAP antagonists that incorporate (R)-tetrahydroisoquinoline in the P3′ subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3–P3′ benzamide linker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1 mg/kg to mice harboring A875 human melanoma tumors. Analog 5, with a polyamine group incorporated at the P2′ thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line.

备注：

IAP是抑制caspase的重要凋亡调节因子，在许多肿瘤中高表达，是治疗癌症的潜在靶点。

5. Discovery of pyridyl sulfonamide 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors for the treatment of metabolic disorders

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5045–5049

DOI: 10.1016/j.bmcl.2014.09.012

公司/组织：BMS

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靶点/作用机制：11β-HSD1抑制剂

摘要原文：

A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11β-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability.

备注：

抑制11β-HSD1以治疗II型糖尿病。

                               
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(by 浮米网)

给楼主调了下，看到字小考眼力