本周共有4篇文献：1、杨森的代谢性谷氨酸盐受体5（mGlu5）调节剂，mGlu5正相变构调节剂有助于治疗精神分裂症。2、阿斯利康的抗疟药；3、Genentech的ITK抑制剂，临床证据显示ITK与过敏性哮喘和其他炎症失调相关。4、DprE1抑制剂，抗分枝杆菌药物。1.Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)J. Med. Chem., 2014, 57 (13), pp 5620–5637
DOI: 10.1021/jm500259z
公司/组织：杨森
候选药物化学结构式/活性：
靶点/作用机制：代谢性谷氨酸盐受体5（mGlu5）调节剂
摘要原文：
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure–activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.
备注：
mGlu5正相变构调节剂有助于治疗精神分裂症。
临床前模型中对精神分裂症和认知能力有效的mGlu5正相变构调节剂如下图所示：
2.Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial AgentsJ. Med. Chem., 2014, 57 (13), pp 5702–5713
DOI: 10.1021/jm500535j
公司/组织：阿斯利康
候选药物化学结构式/活性：
靶点/作用机制：抗疟药
摘要原文：
Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure–activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg–1) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.
备注：
3.Property- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase InhibitorsJ. Med. Chem., 2014, 57 (13), pp 5714–5727
DOI: 10.1021/jm500550e
公司/组织：Genentech
候选药物化学结构式/活性：
靶点/作用机制：ITK抑制剂
摘要原文：
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.
备注：
临床证据显示ITK与过敏性哮喘和其他炎症失调相关。
4.Lead Optimization of 1,4-Azaindoles as Antimycobacterial AgentsJ. Med. Chem., 2014, 57 (13), pp 5728–5737
DOI: 10.1021/jm500571f
公司/组织：阿斯利康
候选药物化学结构式/活性：
靶点/作用机制：DprE1抑制剂
摘要原文：
In a previous report, we described the discovery of 1,4-azaindoles, a chemical series with excellent in vitro and in vivo antimycobacterial potency through noncovalent inhibition of decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1). Nevertheless, high mouse metabolic turnover and phosphodiesterase 6 (PDE6) off-target activity limited its advancement. Herein, we report lead optimization of this series, culminating in potent, metabolically stable compounds that have a robust pharmacokinetic profile without any PDE6 liability. Furthermore, we demonstrate efficacy for 1,4-azaindoles in a rat chronic TB infection model. We believe that compounds from the 1,4-azaindole series are suitable for in vivo combination and safety studies.
备注：抗分枝杆菌药物
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