马上注册，结交更多好友，享用更多功能，让你轻松玩转社区
您需要 登录 才可以下载或查看，没有帐号？立即注册 
x
浮米每周文献快讯：2015年01月（一） 作者：浮米网 来源：浮米网 2015-01-05
1. 原文标题及出处： G-Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5) Agonists Reduce the Production of Proinflammatory Cytokines and Stabilize the Alternative Macrophage Phenotype. J. Med. Chem., 2014, 57 (24), pp 10343–10354 DOI: 10.1021/jm501052c 公司/组织：诺华 候选药物化学结构式/活性：
靶点/作用机制：G蛋白偶联胆汁酸受体1（GPBAR1）激动剂 摘要原文： GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-α and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-α and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation. 备注： GPBAR1与脂代谢、糖代谢以及能量消耗有关，制药公司设计研究GPBAR1以作为糖尿病、高胆固醇血症、高甘油三酯血症以及非酒精性脂肪肝炎的治疗手段。
2. 原文标题及出处： Optimization of Sphingosine-1-phosphate-1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles J. Med. Chem., 2014, 57 (24), pp 10424–10442 DOI: 10.1021/jm5010336 公司/组织：GSK 候选药物化学结构式/活性：
靶点/作用机制：1型1-磷酸鞘氨醇受体(S1P1)激动剂 摘要原文： The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development. 备注： Fingolimod被FDA批准用于治疗复发性-缓和性多发性硬化。
3. 原文标题及出处： Discovery of 2-(Cyclohexylmethylamino)pyrimidines as a New Class of Reversible Valosine Containing Protein Inhibitors J. Med. Chem., 2014, 57 (24), pp 10443–10454 DOI: 10.1021/jm501313x 公司/组织：Genentech 候选药物化学结构式/活性：
靶点/作用机制：含缬酪肽蛋白可逆抑制剂 摘要原文： Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin–proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure–activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity. 备注： 含缬酪肽蛋白(VCP)通过转接蛋白将ATP水解释放的能量转移到底物以行使一系列细胞功能。许多肿瘤中VCP含量增高，且与预后差相关。此外，VCP还与神经退行性疾病相关。
4. 原文标题及出处： Identification of Potent and Selective Hydantoin Inhibitors of Aggrecanase-1 and Aggrecanase-2 That Are Efficacious in Both Chemical and Surgical Models of Osteoarthritis J. Med. Chem., 2014, 57 (24), pp 10476–10485 DOI: 10.1021/jm501522n 公司/组织：礼来 候选药物化学结构式/活性：
靶点/作用机制：聚蛋白多糖酶-1/-2抑制剂 摘要原文： A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats. 备注： 与关节炎相关。
5. 原文标题及出处： Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2–p53 Interaction J. Med. Chem., 2014, 57 (24), pp 10499–10511 DOI: 10.1021/jm501550p 公司/组织：Amgen 候选药物化学结构式/活性：
靶点/作用机制：MDM2–p53相互作用抑制剂 摘要原文： Structure-based rational design and extensive structure–activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2–p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1. 备注：
6. 原文标题及出处： Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes J. Med. Chem., 2014, 57 (24), pp 10512–10526 DOI: 10.1021/jm5016022 公司/组织：辉瑞 候选药物化学结构式/活性：
靶点/作用机制：乙酰辅酶A羧化酶抑制剂 摘要原文： Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease. 备注：
7. 原文标题及出处： Discovery of Cytotoxic Dolastatin 10 Analogues with N-Terminal Modifications J. Med. Chem., 2014, 57 (24), pp 10527–10543 DOI: 10.1021/jm501649k 公司/组织：辉瑞 候选药物化学结构式/活性：
靶点/作用机制：海兔毒素10类似物 摘要原文： Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody–drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with α,α-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design. 备注： 海兔毒素10是有效的细胞毒性微管抑制剂。
| 
|手机版|药群论坛
( 蜀ICP备15007902号 )
收藏
支持
反对