浮米每周文献快讯：2015年06月（一）

浮米每周文献快讯：2015年06月（一）

1. 原文标题及出处：Discovery, Synthesis, and Molecular Pharmacology of Selective Positive Allosteric Modulators of the δ-Opioid Receptor

J. Med. Chem., 2015, 58 (10), pp 4220–4229

DOI: 10.1021/acs.jmedchem.5b00007

公司/组织：Bristol-Myers Squibb

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：δ-阿片受体调节剂

摘要原文：

Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthostericagonistsleu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.

备注：

δ-阿片受体属于A类GPCRs，有7个跨膜结构域。该受体的激动剂在慢性疼痛模型中显示出镇痛的作用，此外，还具有潜在的抗抑郁的药效。

2. 原文标题及出处：

Discovery of a High Affinity and Selective Pyridine Analog as a Potential Positron Emission Tomography Imaging Agent for Cannabinoid Type 2 Receptor

J. Med. Chem., 2015, 58 (10), pp 4266–4277

DOI: 10.1021/acs.jmedchem.5b00283

公司/组织：Roche

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：大麻素II型受体正电子发射断层扫描成像剂

摘要原文：

As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([11C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments. Furthermore, 16 was evaluated in a lipopolysaccharid (LPS) induced murine model of neuroinflammation. Brain radioactivity was strikingly higher in the LPS-treated mice than the control mice. Compound 16 is a promising radiotracer for imaging CB2 in rodents. It might serve as a tool for the investigation of CB2 receptor expression levels in healthy tissues and different neuroinflammatory disorders in humans.

备注：

内源性大麻素系统与多个生理、病例机理相关，是一个较为复杂且严格调控的系统。已知的大麻素受体有CB1和CB2。CB2在神经炎症疾病中发挥重要作用，是一个潜在的治疗靶点，也是帕金森和阿尔兹海默、多发性硬化和肌萎缩性脊髓侧索硬化症PET成像靶点。

3. 原文标题及出处：

Improving the Pharmacokinetic and CYP Inhibition Profiles of Azaxanthene-Based Glucocorticoid Receptor Modulators—Identification of (S)-5-(2-(9-Fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanamido)-N-(tetrahydro-2H-pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341)

J. Med. Chem., 2015, 58 (10), pp 4278–4290

DOI: 10.1021/acs.jmedchem.5b00257

公司/组织：Bristol-Myers Squibb

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：糖皮质激素受体调节剂

摘要原文：

An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a–b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).

备注：

糖皮质激素诸如氢化可的松和地塞米松已被用于治疗自身免疫和炎性疾病超过60年。但是，长期使用糖皮质激素可带来许多副作用，包括糖尿病、高血糖和骨质疏松等。

4. 原文标题及出处：

The Discovery and Characterization of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Potentiator N-{(3S,4S)-4-[4-(5-Cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242)

J. Med. Chem., 2015, 58 (10), pp 4291–4308

DOI: 10.1021/acs.jmedchem.5b00300

公司/组织：辉瑞

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：α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体增效剂

摘要原文：

A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

备注：

AMPA受体介导快速的谷氨酸兴奋神经递质在中枢神经的释放，与突触功能的动态调节也有关。AMPAR增效剂在海马/皮质功能和记忆研究动物模型以及一些小临床试验中显示出预知特性。

5. 原文标题及出处：

Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

J. Med. Chem., 2015, 58 (10), pp 4309–4324

DOI: 10.1021/acs.jmedchem.5b00308

公司/组织：Amakem Therapeutics

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：ROCK抑制剂

摘要原文：

ROCK1 and ROCK2 play important roles in numerous cellular functions, including smooth muscle cell contraction, cell proliferation, adhesion, and migration. Consequently, ROCK inhibitors are of interest for treating multiple indications including cardiovascular diseases, inflammatory and autoimmune diseases, lung diseases, and eye diseases. However, systemic inhibition of ROCK is expected to result in significant side effects. Strategies allowing reduced systemic exposure are therefore of interest. In a continuing effort toward identification of ROCK inhibitors, we here report the design, synthesis, and evaluation of novel soft ROCK inhibitors displaying an ester function allowing their rapid inactivation in the systemic circulation. Those compounds display subnanomolar activity against ROCK and strong differences of functional activity between parent compounds and expected metabolites. The binding mode of a representative compound was determined experimentally in a single-crystal X-ray diffraction study. Enzymes responsible for inactivation of these compounds once they enter systemic circulation are also discussed.

备注：

ROCK也成为Rho激酶，在许多细胞过程中发挥重要角色。ROCk抑制剂有望用于治疗多种疾病，包括高血压、肺动脉高压、炎性和自身免疫疾病等。

(by 浮米网)