【行业】浮米每周文献快讯：2014年6月（二）

【行业】浮米每周文献快讯：2014年6月（二）

2014-06-10 浮米hfoom

1. Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2871–2876

DOI: 10.1016/j.bmcl.2014.04.095

公司/组织：Theravance, Inc.

候选药物化学结构式/活性：

                               
登录/注册后可看大图

靶点/作用机制：长效β2肾上腺素能受体激动剂

摘要原文：

A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing.

备注：

                               
登录/注册后可看大图

2. Solving time-dependent CYP3A4 inhibition for a series of indole-phenylacetic acid dual antagonists of the PGD2 receptors CRTH2 and DP

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2877–2880

DOI: 10.1016/j.bmcl.2014.04.092

公司/组织：Amgen, Inc.

候选药物化学结构式/活性：

                               
登录/注册后可看大图

靶点/作用机制：CRTH2/DP双拮抗剂

摘要原文：

Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI). Hypothesizing that the source of TDI was the indole core we modified the 1,2,3-substitution to eventually afford a highly potent modulator of CRTH2 and DP which did not exhibit TDI.

备注：

CRTH2和DP是和过敏反应相关的药物靶点。

3. Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2885–2891

DOI: 10.1016/j.bmcl.2014.04.089

公司/组织：Amgen Inc

候选药物化学结构式/活性：

                               
登录/注册后可看大图

靶点/作用机制：视黄醇结合蛋白4（RBP4）

摘要原文：

Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4–TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.

备注：

RBP4能导致胰岛素耐受，降低RBP4水平能改善胰岛素敏感性。

4. Discovery of N-sulfonyl-7-azaindoline derivatives as potent, orally available and selective M4 muscarinic acetylcholine receptor agonists

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2909–2912

DOI: 10.1016/j.bmcl.2014.04.083

公司/组织：大日本住友制药

候选药物化学结构式/活性：

                               
登录/注册后可看大图

靶点/作用机制：选择性M4毒蕈碱乙酰胆碱受体（mAChR）激动剂

摘要原文：

We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1–10 mg/kg, po).

备注：

                               
登录/注册后可看大图

5. Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40 agonists

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2949–2953

DOI: 10.1016/j.bmcl.2014.04.065

公司/组织：日本第一三共株式会社（Daiichi Sankyo Company）

候选药物化学结构式/活性：

                               
登录/注册后可看大图

靶点/作用机制：GPR40激动剂

摘要原文：

The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia.

备注：

GPR40是治疗II型糖尿病的新靶点。

(by 浮米网)