【浮米每周文献快讯：2014年7月（一）】1、BMS的糖皮质激素受体激动剂；2、诺华的CXCR2受体拮抗剂，趋化因子IL-8与COPD相关，因此，研发IL-8活化的趋化因子受体CXCR1和CXCR2拮抗剂；3、BM的SXa因子抑制剂；4、礼来的维他命D受体（VDR），调节维他命D受体有助于治疗骨质酥松。
1. Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonistsBioorganic & Medicinal Chemistry Letters 24 (2014) 3268–3273
DOI: 10.1016/j.bmcl.2014.06.010
公司/组织：Bristol-Myers Squibb
候选药物化学结构式/活性：
靶点/作用机制：糖皮质激素受体激动剂
摘要原文：
Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.
备注：
2. The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonistsBioorganic & Medicinal Chemistry Letters 24 (2014) 3285–3290
DOI: 10.1016/j.bmcl.2014.06.011
公司/组织：诺华
候选药物化学结构式/活性：
靶点/作用机制：CXCR2受体拮抗剂
摘要原文：
A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrimidine 2-((2,6-dichlorobenzyl)thio)-5-isocyano-6-phenylpyrimidin-4-ol 4, resulting in the discovery of CXCR2 receptor antagonist 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol 24. The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety.
备注：
趋化因子IL-8与COPD相关，因此，研发IL-8活化的趋化因子受体CXCR1和CXCR2拮抗剂。
已报道的CXCR2拮抗剂：
3. Orally bioavailable factor Xa inhibitors containing alpha-substituted gem-dimethyl P4 moietiesBioorganic & Medicinal Chemistry Letters 24 (2014) 3341–3345
DOI: 10.1016/j.bmcl.2014.05.101
公司/组织：BMS
候选药物化学结构式/活性：
靶点/作用机制：Xa因子抑制剂
摘要原文：
In an effort to identify a potential back-up to apixaban (Eliquis®), we explored a series of diversified P4 moieties. Several analogs with substituted gem-dimethyl moieties replacing the terminal lactam of apixaban were identified which demonstrated potent FXa binding affinity (FXa Ki), good human plasma anticoagulant activity (PT EC2x), cell permeability, and oral bioavailability.
备注：
已报道的抗血凝药
4. HDX reveals unique fragment ligands for the vitamin D receptorBioorganic & Medicinal Chemistry Letters 24 (2014) 3459–3463
DOI: 10.1016/j.bmcl.2014.05.070
公司/组织：礼来
候选药物化学结构式/活性：
靶点/作用机制：维他命D受体（VDR）
摘要原文：
Modulation of the vitamin D receptor (VDR) with a ligand has the potential to be useful for the oral treatment of osteoporosis. One component of our lead generation strategy to identify synthetic ligands for VDR included a fragment based drug design approach. Screening of ligands in a VDR fluorescence polarization assay and a RXR/VDR conformation sensing assay resulted in the identification of multiple fragment hits (lean >0.30). These fragment scaffolds were subsequently evaluated for interaction with the VDR ligand binding domain using hydrogen–deuterium exchange (HDX) mass spectrometry. Significant protection of H/D exchange was observed for some fragments in helixes 3, 7, and 8 of the ligand binding domain, regions which are similar to those seen for the natural hormone VD3. The fragments appear to mimic the A-ring of VD3 thereby providing viable starting points for synthetic expansion.
备注：
调节维他命D受体有助于治疗骨质酥松。
(by 浮米网)
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