浮米每周文献快讯：2015年六月（三）

浮米每周文献快讯：2015年六月（三）前沿        作者：浮米网 来源：浮米网  2015-06-16 0评论

1. 原文标题及出处：

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis

J. Med. Chem., 2015, 58 (11), pp 4462–4482

DOI: 10.1021/jm5018175

公司/组织：Amgen

候选药物化学结构式/活性：

                               
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靶点/作用机制：葡萄糖激酶及相关调节蛋白(GK-GKRP)相互作用阻断剂

摘要原文：

The glucokinase–glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure–activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.

备注：

葡萄糖激酶在葡萄糖内稳态中发挥重要作用。葡萄糖激酶激活剂（GKAs）被认为是有效的糖尿病类药。GKAs虽然有效，但是具有一些潜在的风险，如低血糖等。而GK-GKRP有望能克服相应的副作用。

2. 原文标题及出处：

Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products

J. Med. Chem., 2015, 58 (11), pp 4581–4589

DOI: 10.1021/acs.jmedchem.5b00128

公司/组织：辉瑞

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靶点/作用机制：

摘要原文：

Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthesis of cyclic hexapeptide diastereomers containing γ-amino acids (e.g., statines) and systematically investigate their structure–permeability relationships. These compounds were much more water-soluble and, in many cases, were both more membrane permeable and more stable to liver microsomes than a similar non-statine-containing derivative. Permeability correlated well with the extent of intramolecular hydrogen bonding observed in the solution structures determined in the low-dielectric solvent CDCl3, and one compound showed an oral bioavailability of 21% in rat. Thus, the incorporation of γ-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.

备注：

针对多肽类药物的ADME性质改进。

3. 原文标题及出处：

Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist

J. Med. Chem., 2015, 58 (11), pp 4648–4664

DOI: 10.1021/acs.jmedchem.5b00217

公司/组织：Eisai

候选药物化学结构式/活性：

                               
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靶点/作用机制：食欲素受体拮抗剂

摘要原文：

The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure–activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.

备注：

目前对失眠的有效治疗仍很有限。食欲素A和B（下视丘分泌素1和2）是食欲素/下视丘分泌素受体(OXRs )的内源性神经多肽配体。食欲素/下视丘分泌素受体能调节睡眠/唤醒周期，是治疗失眠的有效靶点。

4. 原文标题及出处：

Crystal Structures of mPGES-1 Inhibitor Complexes Form a Basis for the Rational Design of Potent Analgesic and Anti-Inflammatory Therapeutics

J. Med. Chem., 2015, 58 (11), pp 4727–4737

DOI: 10.1021/acs.jmedchem.5b00330

公司/组织：礼来

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靶点/作用机制：微粒体前列腺素E合成酶1（mPGES-1）抑制剂

摘要原文：

Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure–activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.

备注：

抑制mPGES-1可治疗疼痛、炎症和一些癌症，而不会阻断COX-2催化的抗血栓形成的环前列腺素的合成。

5. 原文标题及出处：

Structure–Activity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors

J. Med. Chem., 2015, 58 (11), pp 4749–4770

DOI: 10.1021/acs.jmedchem.5b00407

公司/组织：诺华

候选药物化学结构式/活性：

                               
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靶点/作用机制：CYP11B2/ CYP11B1抑制剂

摘要原文：

CYP11B2, the aldosterone synthase, and CYP11B1, the cortisol synthase, are two highly homologous enzymes implicated in a range of cardiovascular and metabolic diseases. We have previously reported the discovery of LCI699, a dual CYP11B2 and CYP11B1 inhibitor that has provided clinical validation for the lowering of plasma aldosterone as a viable approach to modulate blood pressure in humans, as well normalization of urinary cortisol in Cushing’s disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physicochemical properties. Structure–activity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of preclinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against CYP11B2 and CYP11B1, although emerging structure–selectivity relationships were noted leading to more CYP11B1-selective analogs.

备注：

CYP11B1将脱氧皮质醇转化为皮质醇；CYP11B2则将11-去氧皮质酮转化为醛固酮。血液醛固酮水平的提高与高血压相关。

6. 原文标题及出处：

Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2

J. Med. Chem., 2015, 58 (11), pp 4790–4801

DOI: 10.1021/acs.jmedchem.5b00466

公司/组织：阿斯利康

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靶点/作用机制：ERK1/2抑制剂

摘要原文：

The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.

备注：

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