浮米每周文献快讯：2014年11月（二）

浮米每周文献快讯：2014年11月（二） 作者：浮米网 来源：浮米网  2014-11-24

1. Histone deacetylase inhibitors derived from 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine and related heterocycles selective for the HDAC6 isoform

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5450–5454

doi:10.1016/j.bmcl.2014.10.022

公司/组织：Takeda Pharmaceuticals

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靶点/作用机制：HDAC6抑制剂

摘要原文：

Acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide are potent sub-type selective HDAC6 inhibitors. Constrained heterocyclic analogs based on 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine show further enhanced HDAC6 selectivity and inhibitory activity in cells. Homology models suggest that the heterocyclic spacer can more effectively access the wider catalytic channel of HDAC6 compared to other HDAC sub-types.

备注：

HDAC6的底物包括α微管蛋白、皮动蛋白以及Hsp90，介导在肿瘤发生、生长和转移中的重要细胞功能，还与自噬相关。

2. Discovery of potent iminoheterocycle BACE1 inhibitors

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5455–5459

doi:10.1016/j.bmcl.2014.10.006

公司/组织：默克

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靶点/作用机制：β位淀粉样前体蛋白分泌酶BACE1抑制剂

摘要原文：

The synthesis of a series of iminoheterocycles and their structure–activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Aβ40 levels upon subcutaneous and oral administration to rats.

备注：

用于治疗阿尔兹海默病。

3. The discovery of avanafil for the treatment of erectile dysfunction: A novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5460–5465

doi:10.1016/j.bmcl.2014.10.008

公司/组织：Mitsubishi Tanabe Pharma Corporation田边三菱制药株式会社

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靶点/作用机制：磷酸二酯酶-5（PDE5）抑制剂

摘要原文：

Novel pyrimidine-5-carboxamide derivatives bearing a 3-chloro-4-methoxybenzylamino group at the 4-position were identified as potent and highly selective phosphodiesterase 5 inhibitors. Among them, we successfully found 10j (avanafil) which exhibited a potent relaxant effect on isolated rabbit cavernosum (EC30 = 2.1 nM) and a high isozyme selectivity.

备注：

许多口服PDE5抑制剂已被用于治疗性功能障碍ED的一线治疗。

4.  Novel tricyclic pyrazolopyrimidines as potent and selective GPR119 agonists

doi:10.1016/j.bmcl.2014.10.010

公司/组织：诺华

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靶点/作用机制：GPR119激动剂

摘要原文：

Systematic SAR optimization of the GPR119 agonist lead 1, derived from an internal HTS campaign, led to compound 29. Compound 29 displays significantly improved in vitro activity and oral exposure, leading to GLP1 elevation in acutely dosed mice and reduced glucose excursion in an OGTT study in rats at doses ⩾10 mg/kg.

备注：

                               
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5. The effect of pKa on pyrimidine/pyridine-derived histamine H4 ligands

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5489–5492

doi:10.1016/j.bmcl.2014.10.013

公司/组织：杨森

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靶点/作用机制：组胺H4受体拮抗剂

摘要原文：

During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.

备注：

                               
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6. 2-Aminopyrimidin-4(1H)-one as the novel bioisostere of urea: Discovery of novel and potent CXCR2 antagonists

doi:10.1016/j.bmcl.2014.10.003

公司/组织：GSK

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靶点/作用机制：CXCR2拮抗剂

摘要原文：

2-Aminopyrimidin-4(1H)-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1H)-ones led to the discovery of the novel and potent CXCR2 antagonist 3e. 2-Aminopyrimidin-4(1H)-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas.

备注：

CXCR2拮抗剂被用于治疗COPD、急性呼吸窘迫综合征和风湿性关节炎等免疫疾病。

7. 7-(4-Alkylidenylpiperidinyl)-quinolone bacterial topoisomerase inhibitors

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5502–5506

doi:10.1016/j.bmcl.2014.10.014

公司/组织：杨森

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靶点/作用机制：细菌拓扑异构酶抑制剂

摘要原文：

Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.

备注：

喹诺酮类被广泛用于抗菌药物。

(by 浮米网)

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