本周全球知名药厂共有9篇文献发表。如杨森的磷酸二酯酶10A（PDE10A）抑制剂的研究，辉瑞非甾体盐皮质激素受体（MR）拮抗剂的研究，Genentech 的ITK抑制剂，用于哮喘等。1. Discovery of Novel 2-((Pyridin-3-yloxy)methyl)piperazines as α7 Nicotinic Acetylcholine Receptor Modulators for the Treatment of Inflammatory Disorders
J. Med. Chem., 2014, 57 (10), pp 3966–3983
DOI: 10.1021/jm5004599
公司/组织：Critical Therapeutics, Inc.
候选药物化学结构式/活性：
靶点/作用机制：α7烟碱乙酰胆碱受体（α7 nAChR）调节剂
摘要原文：
Herein we report the design, synthesis, and structure–activity relationships for a new class of α7 nicotinic acetylcholine receptor (nAChR) modulators based on the 2-((pyridin-3-yloxy)methyl)piperazine scaffold. The oxazolo[4,5-b]pyridine, (R)-18, and 4-methoxyphenylurea, (R)-47, were identified as potent and selective modulators of the α7 nAChR with favorable in vitro safety profiles and good oral bioavailability in mouse. Both compounds were shown to significantly inhibit cellular infiltration in a murine model of allergic lung inflammation. Despite the structural and in vivo functional similarities in the compounds, only (R)-18 was shown to be an agonist. Compound (R)-47 demonstrated silent agonist activity. These data support the hypothesis that the anti-inflammatory activity of the α7 nAChR is mediated by a signal transduction pathway that is independent of ion current.
备注：
α7 nAChR与阿尔兹海默病和精神分裂症相关，还与炎症过程相关（例如哮喘和COPD）。
2. Discovery of a Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitor for the Potential Treatment of SchizophreniaJ. Med. Chem., 2014, 57 (10), pp 4196–4212
DOI: 10.1021/jm500073h
公司/组织：杨森
候选药物化学结构式/活性：
靶点/作用机制：磷酸二酯酶10A（PDE10A）抑制剂
摘要原文：
We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure–activity and structure–property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.
备注：
目前大部分精神分裂治疗药物是针对多巴胺D2受体，但是这部分传统治疗并不是对所有患者都有效。需要新型的疗效好且耐受性好的治疗精神分裂类疾病药物。PDE10A能水解cAMP和cGMP，主要分布在脑部。D1多巴胺受体与cAMP的产生为正相关，D2多巴胺受体与cAMP的产生为负相关。通过抑制PDE10A升高cAMP浓度能模拟D1激动和D2拮抗。
3. Identification of (R)-6-(1-(4-Cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic Acid, a Highly Potent and Selective Nonsteroidal Mineralocorticoid Receptor AntagonistJ. Med. Chem., 2014, 57 (10), pp 4273–4288
DOI: 10.1021/jm500206r
公司/组织：辉瑞
候选药物化学结构式/活性：
靶点/作用机制：非甾体盐皮质激素受体（MR）拮抗剂
摘要原文：
A novel series of nonsteroidal mineralocorticoid receptor (MR) antagonists identified as part of our strategy to follow up on the clinical candidate PF-03882845 (2) is reported. Optimization departed from the previously described pyrazoline 3a and focused on improving the selectivity for MR versus the progesterone receptor (PR) as an approach to avoid potential sex-hormone-related adverse effects and improving biopharmaceutical properties. From this effort, (R)-14c was identified as a potent nonsteroidal MR antagonist (IC50 = 4.5 nM) with higher than 500-fold selectivity versus PR and other related nuclear hormone receptors, with improved solubility as compared to 2 and pharmacokinetic properties suitable for oral administration. (R)-14c was evaluated in vivo using the increase of urinary Na+/K+ ratio in rat as a mechanism biomarker of MR antagonism. Treatment with (R)-14c by oral administration resulted in significant increases in urinary Na+/K+ ratio and demonstrated this novel compound acts as an MR antagonist.
备注：
MR过度激活与心血管疾病相关，还与纤维化、炎症和氧化应激相关。
4. Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitorsBioorganic & Medicinal Chemistry Letters 24 (2014) 2448–2452
DOI: 10.1016/j.bmcl.2014.04.023
公司/组织：Genentech Inc.
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：
There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.
备注：
ITK是Tec激酶家族的一员，在T细胞通路中发挥重要作用。ITK抑制剂有望于治疗哮喘。
5. Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitorsBioorganic & Medicinal Chemistry Letters 24 (2014) 2477–2480
DOI: 10.1016/j.bmcl.2014.04.012
公司/组织：Genentech Inc & Array BioPharm
候选药物化学结构式/活性：
靶点/作用机制：BACE1抑制剂
摘要原文：
The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50 = 110 nM) demonstrated a reduction in CSF Aβ in wild type rats after a single dose.
备注：
抑制蛋白酶beta位点APP裂解酶1（BACE1）与治疗阿尔兹海默病有关。
6. 2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonistsBioorganic & Medicinal Chemistry Letters 24 (2014) 2481–2485
DOI: 10.1016/j.bmcl.2014.04.011
公司/组织：Bristol-Myers Squibb
候选药物化学结构式/活性：
靶点/作用机制：P2Y1受体拮抗剂
摘要原文：
Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 μM with 10 μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.
备注：
阻断P2Y1或P2Y12受体能显著抑制血小板凝聚，在治疗血栓上有很大作用。
7. Synthesis and structure–activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonistsBioorganic & Medicinal Chemistry Letters 24 (2014) 2539–2545
DOI: 10.1016/j.bmcl.2014.03.096
公司/组织：Bristol-Myers Squibb
候选药物化学结构式/活性：
靶点/作用机制：GPR119激动剂
摘要原文：
Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R1 attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R2. The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.
备注：
GPR119与糖尿病相关。
8. Structure-based design and synthesis of bicyclic fused-pyridines as MEK inhibitorsBioorganic & Medicinal Chemistry Letters 24 (2014) 2555–2559
DOI: 10.1016/j.bmcl.2014.03.086
公司/组织：上海恒瑞制药
候选药物化学结构式/活性：
靶点/作用机制：
摘要原文：
The MAPK pathway is identified as one of the most important pathways involved in cell proliferation and differentiation. A key kinase in the pathway, the Mitogen-activated protein kinase kinase (MEK) is recognized as a promising target for antitumor drugs. Structure-based design and optimization of known MEK inhibitors resulted in identification of compound 10a as a potent non-ATP competitive MEK inhibitor in both in vitro and in vivo tests.
备注：
9. The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalationBioorganic & Medicinal Chemistry Letters 24 (2014) 2571–2577
DOI: 10.1016/j.bmcl.2014.03.070
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：糖皮质激素受体调节剂
摘要原文：
We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.
备注：
糖皮质激素作为抗炎药物已成功用于治疗多种慢性炎症和自身免疫疾病,包括呼吸道疾病例如哮喘和COPD。糖皮质激素通过结合糖皮质激素受体发挥作用。相比较传统的甾体类，非甾体类糖皮质激素受体调节剂有望于在药效上和安全性上都有提高。
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