浮米每周文献快讯：2015年01月(四)

浮米每周文献快讯：2015年01月(四) 作者：浮米网 来源：浮米网  2015-01-25

1. 原文标题及出处：
Design, Synthesis, and Evaluation of New Thiadiazole-Based Direct Inhibitors of Enoyl Acyl Carrier Protein Reductase (InhA) for the Treatment of Tuberculosis
J. Med. Chem., 2015, 58 (2), pp 613–624
DOI: 10.1021/jm501029r
公司/组织：GSK
候选药物化学结构式/活性：

                               
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靶点/作用机制：烯酰脂酰载体蛋白还原酶
摘要原文：
Mycobacterial enoyl acyl carrier protein reductase (InhA) is a clinically validated target for the treatment of tuberculosis infections, a disease that still causes the death of at least a million people annually. A known class of potent, direct, and competitive InhA inhibitors based on a tetracyclic thiadiazole structure has been shown to have in vivo activity in murine models of tuberculosis infection. On the basis of this template, we have here explored the medicinal chemistry of truncated analogues that have only three aromatic rings. In particular, compounds 8b, 8d, 8f, 8l, and 8n show interesting features, including low nanomolar InhA IC50, submicromolar antimycobacterial potency, and improved physicochemical profiles in comparison with the tetracyclic analogues. From this series, 8d is identified as having the best balance of potency and properties, whereby the resolved 8d S-enatiomer shows encouraging in vivo efficacy.
备注：
治疗肺结核的一线、二线抗分枝杆菌药物在临床使用已超过30年。而由于耐药性和长期使用，急需新的药物和新的治疗配方。

2. 原文标题及出处：
Evaluation of Three Different Families of Bombesin Receptor Radioantagonists for Targeted Imaging and Therapy of Gastrin Releasing Peptide Receptor (GRP-R) Positive Tumors
J. Med. Chem., 2015, 58 (2), pp 682–691
DOI: 10.1021/jm5012066
公司/组织：拜耳
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靶点/作用机制：胃液素释放肽受体拮抗剂
摘要原文：
Two new classes of radiolabeled GRP receptor antagonists are studied and compared with the well-established statine-based receptor antagonist DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM2, 1; DOTA:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; Sta3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid). The bombesin-based pseudopeptide DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ(CHOH-CH2)-(CH2)2-CH3 (RM7, 2), and the methyl ester DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-OCH3 (ARBA05, 3) analogues are labeled with 111In and evaluated in vitro in PC-3 cell line and in vivo in PC-3 tumor-bearing nude mice. Antagonist potency was assessed by immunofluorescence-based receptor internalization and Ca2+ mobilization assays. The conjugates showed good binding affinity, the IC50 value of 2 (3.2 ± 1.8 nM) being 2 and 10 times lower than 1 and 3. Compared to 111In-1, 111In-2 showed higher uptake in target tissues such as pancreas (1.5 ± 0.5%IA/g and 39.8 ± 9.3%IA/g at 4 h, respectively), whereas the compounds had similar tumor uptake (11.5 ± 2.4%IA/g and 11.8 ± 3.9%IA/g at 4h, respectively). The displacement of the radioligand in vivo was different in different receptor positive organs and depended on the displacing peptide.
备注：
利用放射性标示受体拮抗剂。

3. 原文标题及出处：
Structure Guided Lead Generation for M. tuberculosis Thymidylate Kinase (Mtb TMK): Discovery of 3-Cyanopyridone and 1,6-Naphthyridin-2-one as Potent Inhibitors
J. Med. Chem., 2015, 58 (2), pp 753–766
DOI: 10.1021/jm5012947
公司/组织：AstraZeneca
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靶点/作用机制：结核分枝杆菌胸苷激酶抑制剂
摘要原文：
M. tuberculosis thymidylate kinase (Mtb TMK) has been shown in vitro to be an essential enzyme in DNA synthesis. In order to identify novel leads for Mtb TMK, we performed a high throughput biochemical screen and an NMR based fragment screen through which we discovered two novel classes of inhibitors, 3-cyanopyridones and 1,6-naphthyridin-2-ones, respectively. We describe three cyanopyridone subseries that arose during our hit to lead campaign, along with cocrystal structures of representatives with Mtb TMK. Structure aided optimization of the cyanopyridones led to single digit nanomolar inhibitors of Mtb TMK. Fragment based lead generation, augmented by crystal structures and the SAR from the cyanopyridones, enabled us to drive the potency of our 1,6-naphthyridin-2-one fragment hit from 500 μM to 200 nM while simultaneously improving the ligand efficiency. Cyanopyridone derivatives containing sulfoxides and sulfones showed cellular activity against M. tuberculosis. To the best of our knowledge, these compounds are the first reports of non-thymidine-like inhibitors of Mtb TMK.
备注：
结核分枝杆菌胸苷激酶与DNA合成相关，是分枝杆菌存活的重要靶点。

4. 原文标题及出处：
Discovery of AZD6642, an Inhibitor of 5-Lipoxygenase Activating Protein (FLAP) for the Treatment of Inflammatory Diseases
J. Med. Chem., 2015, 58 (2), pp 897–911
DOI: 10.1021/jm501531v
公司/组织：AstraZeneca
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靶点/作用机制：5-脂氧合酶激活蛋白
摘要原文：
A drug discovery program in search of novel 5-lipoxygenase activating protein (FLAP) inhibitors focused on driving a reduction in lipophilicity with maintained or increased ligand lipophilic efficiency (LLE) compared to previously reported compounds led to the discovery of AZD6642 (15b). Introduction of a hydrophilic tetrahydrofuran (THF) ring at the stereogenic central carbon atom led to a significant shift in physicochemical property space. The structure–activity relationship exploration and optimization of DMPK properties leading to this compound are described in addition to pharmacokinetic analysis and an investigation of the pharmacokinetic (PK)–pharmacodynamic (PD) relationship based on ex vivo leukotriene B4 (LTB4) levels in dog. AZD6642 shows high specific potency and low lipophilicity, resulting in a selective and metabolically stable profile. On the basis of initial PK/PD relation measured, a low dose to human was predicted.
备注：
5-脂氧合酶和5-脂氧合酶激活蛋白在白三烯的产生过程中发挥重要作用，利用这两个蛋白的抑制剂都能阻断白三烯的产生。

5. 原文标题及出处：
Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram Positive Activity and Improved Safety Profile
J. Med. Chem., 2015, 58 (2), pp 927–942
DOI: 10.1021/jm501590q
公司/组织：Actelion Pharmaceuticals Limited
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靶点/作用机制：拓扑异构酶抑制剂
摘要原文：
Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K+ channels and hNaV1.5 Na+ channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.
备注：

6. 原文标题及出处：
Discovery of (R)-8-(1-(3,5-Difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the Treatment of PTEN-Deficient Cancers
J. Med. Chem., 2015, 58 (2), pp 943–962
DOI: 10.1021/jm501629p
公司/组织：AstraZeneca
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靶点/作用机制：PI3Kβ和PI3Kδ抑制剂
摘要原文：
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kβ/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.
备注：
I类PI3Ks主要磷酸化PIP2以产生PIP3，而肿瘤抑制因子PTEN则逆转这个过程。

7. 原文标题及出处：
Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.
J. Med. Chem., 2015, 58 (2), pp 978–993
DOI: 10.1021/jm501651a
公司/组织：杨森
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靶点/作用机制：磷酸二酯酶10A（PDE10A）抑制剂
摘要原文：
We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure–activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.
备注：

(by 浮米网)