【转帖】研发每周文献快讯：2014年3月（一）

zhulikou431

1. Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine-3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition.

期刊： J. Med. Chem., 2014, 57 (3), pp 733–758.
DOI：10.1021/jm4014828
公司/组织：阿斯利康
相关候选药物化学结构及活性：
靶点/作用机理：组胺H3受体拮抗剂 （H3R）
摘要原文：A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (50×) with a brain-to-plasma ratio of 3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.
备注：H3R的选择性抑制能降低组胺、去甲肾上腺素、乙酰胆碱和多巴胺水平，已作为与睡眠障碍、注意缺陷多动障碍、妥瑞氏症、关节炎、神经疼痛、代谢失调等疾病相关的药物研发靶点。该文献报道的一系列H3R拮抗剂结构上没有芳香环，与现今已报道的大部分H3R拮抗剂不同。

2. Fragment-Based Identification of Amides Derived from trans-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT).

期刊： J. Med. Chem., 2014, 57 (3), pp 770–792.
DOI：10.1021/jm4015108
公司/组织：基因泰克Genentech, Inc.
相关候选药物化学结构及活性：
靶点/作用机理：烟酰胺磷酸核糖转移酶 （NAMPT）
摘要原文：Potent, trans-2-(pyridin-3-yl)cyclopropanecarboxamide-containing inhibitors of the human nicotinamide phosphoribosyltransferase (NAMPT) enzyme were identified using fragment-based screening and structure-based design techniques. Multiple crystal structures were obtained of initial fragment leads, and this structural information was utilized to improve the biochemical and cell-based potency of the associated molecules. Many of the optimized compounds exhibited nanomolar antiproliferative activities against human tumor lines in in vitro cell culture experiments. In a key example, a fragment lead (13, KD = 51 μM) was elaborated into a potent NAMPT inhibitor (39, NAMPT IC50 = 0.0051 μM, A2780 cell culture IC50 = 0.000 49 μM) which demonstrated encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model.
备注：烟酰胺磷酸核糖转移酶(NAMPT)是生命过程中不可或缺的蛋白,参与NAM-NAD循环通路,对许多疾病如心脑血管疾病、糖尿病、癌症、自身免疫性疾病等有潜在的作用。其抑制剂GMX-1778/CHS828和APO-866/FK866已进入临床测试阶段。

3. Discovery of 7-Tetrahydropyran-2-yl Chromans: β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors That Reduce Amyloid β-Protein (Aβ) in the Central Nervous System.

期刊：J. Med. Chem., 2014, 57 (3), pp 878–902.
DOI：10.1021/jm401635n
公司/组织： Array BioPharma&基因泰克Genentech, Inc.
相关候选药物化学结构及活性：
靶点/作用机理：β-位点淀粉样前体蛋白裂解酶1 （BACE1）
摘要原文：In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2′ sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10–420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aβ1–40 production (5–99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (Cfree,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aβ1–40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.
备注：BACE1与阿尔兹海默病相关，礼来和默克最早开始研究BACE1抑制剂。默克的BACE1抑制剂MK-8931耐受性较好，已进入临床II/III期试验。

4. Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitors.

期刊：J. Med. Chem., 2014, 57 (3), pp 955–969.
DOI：10.1021/jm401670x
公司/组织：Bristol-Myers Squibb
相关候选药物化学结构及活性：
靶点/作用机理：凝血因子Factor Xia
摘要原文：Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.
备注：FXIa 可能作为治疗并预防血栓性栓塞疾病的理想靶点，其治疗相关的出血风险较低。

5. Optimization of Brain Penetrant 11β-Hydroxysteroid Dehydrogenase Type I Inhibitors and in Vivo Testing in Diet-Induced Obese Mice.

期刊： J. Med. Chem., 2014, 57 (3), pp 970–986.
DOI：10.1021/jm4016729
公司/组织：AstraZeneca
相关候选药物化学结构及活性：
靶点/作用机理：I型11β-羟基类固醇脱氢酶（11β-HSD1）
摘要原文：11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome.
备注：目前已报道的关于11β-HSD1的专利应用已超过250份，主要针对代谢综合征。默克的两个化合物已进入临床试验：MK-0916于2004年进入临床II期试验，MK-0736于2005年进入临床II期试验。

6. Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ-Secretase Modulators.

期刊： J. Med. Chem., 2014, 57 (3), pp 1046–1062.
DOI：10.1021/jm401782h
公司/组织：Pfizer
相关候选药物化学结构及活性：
靶点/作用机理：γ-分泌酶调节剂（GSMs）
摘要原文：Herein we describe the design and synthesis of a novel series of γ-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain Aβ42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the γ-secretase complex, thus gaining insight into the binding site of this series of GSMs.
备注：相比较于γ-分泌酶抑制剂，γ-分泌酶调节剂安全谱更好。

7. Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept.

期刊： J. Med. Chem., 2014, 57 (2), pp 309–324.
DOI：10.1021/jm4016735
公司/组织：Amgen
相关候选药物化学结构及活性：
靶点/作用机理：葡萄糖激酶调节蛋白
摘要原文：Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.
备注：葡萄糖激酶(GK)参与葡萄糖平衡的调控，其活性受GKRP的调节。通过阻断GK-GKRP相互作用能达到降血糖的目的。

8. Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles.

期刊： J. Med. Chem., 2014, 57 (2), pp 325–338.
DOI：10.1021/jm4016747
公司/组织：Amgen
相关候选药物化学结构及活性：
靶点/作用机理：葡萄糖激酶调节蛋白
摘要原文：In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.

药仙

好贴，只是草根没兴趣

zhulikou431

药仙 发表于 2014-3-4 20:40
好贴，只是草根没兴趣

我是草根，我很感兴趣

药仙

zhulikou431 发表于 2014-3-4 20:44
我是草根，我很感兴趣

我也是

zhulikou431

药仙 发表于 2014-3-4 20:45
我也是

这些很深的，得有点药物化学的功底

药仙

我喜欢，蒲公英就缺这样的帖子

是非黑人

看看吧，大家都会支持你












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