浮米每周文献快讯：2015年03月(二)

浮米每周文献快讯：2015年03月(二) 作者：浮米网 来源：浮米网  2015-03-15

1. 原文标题及出处：

Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity

J. Med. Chem., 2015, 58 (5), pp 2180–2194

DOI: 10.1021/jm501258m

公司/组织：AbbVie Inc

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：MCL-1抑制剂

摘要原文：

Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.

备注：

MCL-1是BCL-2家族中的一员，在肿瘤中高表达，在肿瘤发生、发展中发挥重要作用。

2. 原文标题及出处：

Discovery of Efficacious Pseudomonas aeruginosa-Targeted Siderophore-Conjugated Monocarbams by Application of a Semi-mechanistic Pharmacokinetic/Pharmacodynamic Model

J. Med. Chem., 2015, 58 (5), pp 2195–2205

DOI: 10.1021/jm501506f

公司/组织：AstraZeneca

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：单卡波姆抗绿脓杆菌抗生素

摘要原文：

To identify new agents for the treatment of multi-drug-resistant Pseudomonas aeruginosa, we focused on siderophore-conjugated monocarbams. This class of monocyclic β-lactams are stable to metallo-β-lactamases and have excellent P. aeruginosa activities due to their ability to exploit the iron uptake machinery of Gram-negative bacteria. Our medicinal chemistry plan focused on identifying a molecule with optimal potency and physical properties and activity for in vivo efficacy. Modifications to the monocarbam linker, siderophore, and oxime portion of the molecules were examined. Through these efforts, a series of pyrrolidinone-based monocarbams with good P. aeruginosa cellular activity (P. aeruginosa MIC90 = 2 μg/mL), free fraction levels (>20% free), and hydrolytic stability (t1/2 ≥ 100 h) were identified. To differentiate the lead compounds and enable prioritization for in vivo studies, we applied a semi-mechanistic pharmacokinetic/pharmacodynamic model to enable prediction of in vivo efficacy from in vitro data.

备注：

绿脓杆菌具有严重的耐药性。

3. 原文标题及出处：

Discovery of Highly Selective Brain-Penetrant Vasopressin 1a Antagonists for the Potential Treatment of Autism via a Chemogenomic and Scaffold Hopping Approach

J. Med. Chem., 2015, 58 (5), pp 2275–2289

DOI: 10.1021/jm501745f

公司/组织：Roche

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：血管加压素1a拮抗剂

摘要原文：

From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable tool compounds which demonstrated a V1a mediated central in vivo effect. This novel series was further optimized through parallel synthesis with a focus on balancing lipophilicity to achieve robust aqueous solubility while avoiding P-gp mediated efflux. These efforts led to the discovery of the highly potent and selective brain-penetrant hV1a antagonist RO5028442 (8) suitable for human clinical studies in people with autism.

备注：

血管加压素是9个氨基酸的环肽。在压力状态下，啮齿动物的大脑中血管加压素释放增多。血管加压素受体拮抗剂能发挥类似抗抑郁药的作用。

4. 原文标题及出处：

Engineering Potent and Selective Analogues of GpTx-1, a Tarantula Venom Peptide Antagonist of the NaV1.7 Sodium Channel

J. Med. Chem., 2015, 58 (5), pp 2299–2314

DOI: 10.1021/jm501765v

公司/组织：Amgen Inc.

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：NaV1.7纳通道拮抗剂

摘要原文：

NaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). NMR structural analysis of the chemically synthesized three disulfide peptide was consistent with an inhibitory cystine knot motif. Alanine scanning of GpTx-1 revealed that residues Trp29, Lys31, and Phe34 near the C-terminus are critical for potent NaV1.7 antagonist activity. Substitution of Ala for Phe at position 5 conferred 300-fold selectivity against NaV1.4. A structure-guided campaign afforded additive improvements in potency and NaV subtype selectivity, culminating in the design of [Ala5,Phe6,Leu26,Arg28]GpTx-1 with a NaV1.7 IC50 value of 1.6 nM and >1000× selectivity against NaV1.4 and NaV1.5.

备注：

NaV1.7与痛觉相关。

5. 原文标题及出处：

Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2

J. Med. Chem., 2015, 58 (5), pp 2326–2349

DOI: 10.1021/jm501778s

公司/组织：AstraZeneca

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：mTORC1&2抑制剂

摘要原文：

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50–pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

备注：

PI3K-Akt-mTOR通路是癌症中最为异常调控的通路。

6. 原文标题及出处：

Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors

J. Med. Chem., 2015, 58 (5), pp 2417–2430

DOI: 10.1021/jm501913a

公司/组织：Amgen

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：c-Met抑制剂

摘要原文：

The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.

备注：

c-Met在许多肿瘤中异常表达或有突变，抑制c-Met活性是治疗c-Met激活的肿瘤的一个有效途径。

(by 浮米网)