【前沿】浮米每周文献快讯：2015年04月（二）

【前沿】浮米每周文献快讯：2015年04月（二）2015-04-13 [url=]浮米hfoom[/url]

                               
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1. 原文标题及出处：

Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

J. Med. Chem., 2015, 58 (7), pp 3223–3252

DOI: 10.1021/acs.jmedchem.5b00191

公司/组织：Pfizer

候选药物化学结构式/活性：

                               
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靶点/作用机制：BACE1抑制剂

摘要原文：

In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer’s disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug–drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.

备注：

BACE1是治疗阿尔兹海默病的重要靶点，也有很多相关抑制剂进入临床。相关副作用包括肝毒性和眼毒性。新一代的BACE1抑制剂需要具有良好的CNS通透性、更少的副作用并且低剂量等特性。

2. 原文标题及出处：

Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT): Cocrystal Structures of Pyrazolopyrans with Potent Blood- and Liver-Stage Activities

J. Med. Chem., 2015, 58 (7), pp 3117–3130

DOI: 10.1021/jm501987h

公司/组织：GlaxoSmithKline

候选药物化学结构式/活性：

                               
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靶点/作用机制：疟原虫丝氨酸氢甲基转移酶抑制剂

摘要原文：

Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 Å resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.

备注：

疟疾是全球较为严重的感染病之一，而目前所用的抗疟原虫药出现了严重的耐药性。因此，需要新型的抗疟原虫药。

3. 原文标题及出处：

X-ray Crystal Structures of Escherichia coli RNA Polymerase with Switch Region Binding Inhibitors Enable Rational Design of Squaramides with an Improved Fraction Unbound to Human Plasma Protein

J. Med. Chem., 2015, 58 (7), pp 3156–3171

DOI: 10.1021/acs.jmedchem.5b00050

公司/组织：AstraZeneca

候选药物化学结构式/活性：

                               
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靶点/作用机制：RNA多聚酶抑制剂

摘要原文：

Squaramides constitute a novel class of RNA polymerase inhibitors of which genetic evidence and computational modeling previously have suggested an inhibitory mechanism mediated by binding to the RNA polymerase switch region. An iterative chemistry program increased the fraction unbound to human plasma protein from below minimum detection levels, i.e., <1% to 4–6%, while retaining biochemical potency. Since in vitro antimicrobial activity against an efflux-negative strain of Haemophilus influenzae was 4- to 8-fold higher, the combined improvement was at least 20- to 60-fold. Cocrystal structures of Escherichia coli RNA polymerase with two key squaramides showed displacement of the switch 2, predicted to interfere with the conformational change of the clamp domain and/or with binding of template DNA, a mechanism akin to that of natural product myxopyronin. Furthermore, the structures confirmed the chemical features required for biochemical potency. The terminal isoxazole and benzyl rings bind into distinct relatively narrow, hydrophobic pockets, and both are required for biochemical potency. In contrast, the linker composed of squarate and piperidine accesses different conformations in their respective cocrystal structures with RNA polymerase, reflecting its main role of proper orientation of the aforementioned terminal rings. These observations further explain the tolerance of hydrophilic substitutions in the linker region that was exploited to improve the fraction unbound to human plasma protein while retaining biochemical potency.

备注：

天然抗菌物 myxopyronin 和方酰胺化学结构不同，却结合RNA多聚酶同一位点。而新结合位点的发现可以为设计新型抗菌素提供依据。

(by 浮米网)