浮米每周文献快讯：2015年七月（一）

浮米每周文献快讯：2015年七月（一）        作者：浮米网 来源：浮米网  2015-07-08

1. 原文标题及出处：
Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3157–3163
doi:10.1016/j.bmcl.2015.06.004
公司/组织：杨森
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：P2X7拮抗剂
摘要原文：
The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50 = 7.7 nM) and 7u (P2X7 IC50 = 7.7 nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
备注：
P2X7离子通道是ATP-门控的嘌呤受体。P2X7受体与IL-1β以及其他促炎性细胞因子的释放有关，进而与外周炎症类疾病相关，包括炎性疼痛、风湿性关节炎以及骨质酥松。此外，还可能与一些神经炎症相关，如阿尔兹海默、癫痫等。

2. 原文标题及出处：
Discovery and characterization of a potent and selective EP4 receptor antagonist
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3176–3178
doi:10.1016/j.bmcl.2015.05.091
公司/组织：礼来
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：EP4受体拮抗剂
摘要原文：
EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.
备注：
前列腺素E2（PGE2）通过作用于类视紫红质G蛋白偶联受体EP1-4与包括炎症、癌症以及支气管炎等疾病相关。拮抗EP4是控制炎症症状的治疗手段。

3. 原文标题及出处：
Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα)
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3189–3193
doi:10.1016/j.bmcl.2015.05.093
公司/组织：阿斯利康
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：PI4KIIIα抑制剂
摘要原文：
The discovery and optimisation of novel, potent and selective small molecule inhibitors of the α-isoform of type III phosphatidylinositol-4-kinase (PI4Kα) are described. Lead compounds show cellular activity consistent with their PI4Kα potency inhibiting the accumulation of IP1 after PDGF stimulation and reducing cellular PIP, PIP2 and PIP3 levels. Hence, these compounds are useful in vitro tools to delineate the complex biological pathways involved in signalling through PI4Kα.
备注：
PI4Ks催化生成磷脂酰肌醇-4-磷酸（PI4P）。哺乳动物中4个PI4K亚型被分为两类：II型（PI4KIIα and β）和III型（PI4KIIIα and β）。有研究指出PI4KIIIα及PI4P与细菌增殖有关。

4. 原文标题及出处：
Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3203–3207
doi:10.1016/j.bmcl.2015.05.097
公司/组织：默克
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：白介素-1受体相关激酶-4(IRAK4)抑制剂
摘要原文：
IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases
备注：
IRAK4是丝/苏氨酸激酶，作为白介素-1/Toll样受体(IL-1/TLR)信号通路的一部分，在非特异性免疫中发挥重要作用。

5. 原文标题及出处：
Whole cell screen based identification of spiropiperidines with potent antitubercular properties
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3234–3245
doi:10.1016/j.bmcl.2015.05.087
公司/组织：阿斯利康 & 赛诺菲
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：抗结核杆菌
摘要原文：
Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[indene-1,4′-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[chromene-2,4′-piperidine] (abbr. spirochromenes) and 1′-benzylspiro[indole-1,4′-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed ⩾4 log10 kill (at 2–12 μM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.
备注：
由于多药耐药性问题以及非复制型状态存在的病原体（NRP）导致的慢性或潜伏性感染，肺结核日益成为一个较难治愈的疾病。研发针对复制型以及NRP型结核杆菌的抗菌药是TB药物研发的热点。

6. 原文标题及出处：
Design, synthesis and evaluation of MCH receptor 1 antagonists—Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3264–3269
doi:10.1016/j.bmcl.2015.05.077
公司/组织：勃林格殷格翰
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：黑色素浓集激素（MCH）受体1拮抗剂
摘要原文：
Despite recent approvals of anti-obesity drugs there is still a high therapeutic need for alternative options with higher efficacy in humans. As part of our MCH-R1 antagonist program for the treatment of obesity, a series of biphenylacetamide HTS hits was evaluated. Several issues of the initial lead structures had to be resolved, such as potency, selectivity over related GPCRs and P-gp efflux limiting brain exposure in this series. We could demonstrate that all parameters can be significantly improved by structural modifications resulting in BI 414 as a potent and orally available MCH-R1 antagonist tool compound with acceptable in vivo efficacy in an animal model of obesity.
备注：
肥胖者患II型糖尿病、血脂异常、冠心病、中风等代谢型疾病的危险较高。MCH作用于MCHR1和MCHR2，与食物摄取有关。

7. 原文标题及出处：
Design, synthesis and evaluation of MCH receptor 1 antagonists—Part II: Optimization of pyridazines toward reduced phospholipidosis and hERG inhibition
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3270–3274
doi:10.1016/j.bmcl.2015.05.074
公司/组织：勃林格殷格翰
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：黑色素浓集激素（MCH）受体1拮抗剂
摘要原文：
Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis.
备注：

8. 原文标题及出处：
Design, synthesis and evaluation of MCH receptor 1 antagonists—Part III: Discovery of pre-clinical development candidate BI 186908
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3275–3280
doi:10.1016/j.bmcl.2015.05.065
公司/组织：勃林格殷格翰
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：黑色素浓集激素（MCH）受体1拮抗剂
摘要原文：
Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development.
备注：

9. 原文标题及出处：
Novel broad-spectrum inhibitors of bacterial methionine aminopeptidase
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3301–3306
doi:10.1016/j.bmcl.2015.05.061
公司/组织：阿斯利康
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：细菌甲硫氨酸胺基肽酶抑制剂
摘要原文：
With increasing emergence of multi-drug resistant infections, there is a dire need for new classes of compounds that act through unique mechanisms. In this work, we describe the discovery and optimization of a novel series of inhibitors of bacterial methionine aminopeptidase (MAP). Through a high-throughput screening campaign, one azepinone amide hit was found that resembled the native peptide substrate and possessed moderate biochemical potency against three bacterial isozymes. X-ray crystallography was used in combination with substrate-based design to direct the rational optimization of analogs with sub-micromolar potency. The novel compounds presented here represent potent broad-spectrum biochemical inhibitors of bacterial MAP and have the potential to lead to the development of new medicines to combat serious multi-drug resistant infections.
备注：
甲硫氨酸胺基肽酶与蛋白质后修饰有关，是研发新型广谱抗菌药的有效靶点。

(by 浮米网)

感谢分享！！

学习了，谢谢分享

感谢分享