1. 原文标题及出处：
2-Aryl-3-methyloctahydrophenanthrene-2,3,7-triols as Potent Dissociated Glucocorticoid Receptor Agonists
J. Med. Chem., 2015, 58 (6), pp 2658–2677
DOI: 10.1021/jm501601b
公司/组织：Pfizer
候选药物化学结构式/活性：
靶点/作用机制：游离的糖皮质激素受体激动剂
摘要原文：
A significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy assay measuring repression of IL-1 induced MMP-13 expression was 3.5 nM, exhibiting 87% of the maximal effect of dexamethasone (DEX). It displayed a dissociated profile by exhibiting 42% of the maximal effect of DEX in a mouse mammary tumor virus (MMTV) luciferase reporter transactivation assay. Compound 13 and analogues containing heterocyclic replacements for the C2 phenyl and modified B rings showed high repression of TNFα production in human whole blood, with IC50 values (43–167 nM) approaching the level of DEX (21 nM). On the basis of X-ray structures and force field calculations, the overall potency of this series was attributed to a favorable conformation of the C2α phenyl, induced by the neighboring C3α methyl.
备注：
糖皮质激素受体激动剂是有效的炎症和自身免疫疾病的口服治疗手段，但是具有明显的副作用。利用游离的激动剂可以克服这一问题。
2. 原文标题及出处：
Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design
J. Med. Chem., 2015, 58 (6), pp 2678–2702
DOI: 10.1021/jm501833t
公司/组织：Pfizer
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 identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired absorption, distribution, metabolism, and excretion (ADME) properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Upon oral administration, these inhibitors exhibit robust brain availability and are efficacious in lowering central Amyloid β (Aβ) levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Aβ-derived plaques. Most importantly, evaluation of 36 in a 2-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.
备注：
3. 原文标题及出处：
Discovery of Novel P1 Groups for Coagulation Factor VIIa Inhibition Using Fragment-Based Screening
J. Med. Chem., 2015, 58 (6), pp 2799–2808
DOI: 10.1021/jm501982k
公司/组织：Bristol-Myers Squibb
候选药物化学结构式/活性：
靶点/作用机制：凝血因子VIIa抑制剂
摘要原文：
A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.
备注：
组织凝血活酶-VIIa因子原酶复合物(TF–factor VIIa)是治疗血栓的潜在靶点，抑制这个复合物能减少出血的副作用。VIIa因子的催化域是具有类似胰蛋白酶结构的丝氨酸蛋白酶。
4. 原文标题及出处：
Design and Synthesis of Orally Bioavailable Aminopyrrolidinone Histone Deacetylase 6 Inhibitors
J. Med. Chem., 2015, 58 (6), pp 2809–2820
DOI: 10.1021/jm502011f
公司/组织：Roche
候选药物化学结构式/活性：
靶点/作用机制：组蛋白去乙酰化酶6（HDAC6）抑制剂
摘要原文：
Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6-selective inhibitors as chemical biology tools and ultimately as new therapeutic agents. Herein we report the design, synthesis, and phenotypic screening of a novel class of 3-aminopyrrolidinone-based hydroxamic acids as HDAC6 inhibitors. In particular, the α-methyl-substituted enantiomer 33 (3-S) showed significant in-cell tubulin acetylation (Tub-Ac) with an EC50 of 0.30 μM but limited impact on p21 levels at various concentrations. In enzyme inhibition assays, 33 demonstrated high selectivity for HDAC6 with an IC50 of 0.017 μM and selectivity indexes of 10 against HDAC8 and over 4000 against HDAC1–3 isoforms. Moreover, 33 has suitable drug metabolism and pharmacokinetics properties compared with other hydroxamic acid-based HDAC inhibitors, warranting further biological studies and development as a selective HDAC6 inhibitor.
备注：
HDAC6被作为治疗癌症、阿尔兹海默和自身免疫疾病的靶点。
5. 原文标题及出处：
Design, Synthesis, and Evaluation of NO-Donor Containing Carbonic Anhydrase Inhibitors To Lower Intraocular Pressure
J. Med. Chem., 2015, 58 (6), pp 2821–2833
DOI: 10.1021/acs.jmedchem.5b00043
公司/组织：Pfizer
候选药物化学结构式/活性：
靶点/作用机制：碳酸酐酶抑制剂
摘要原文：
The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).
备注：
青光眼主要病理学表现为眼内压升高，而降低眼内压能控制青光眼并避免视力丧失。抑制碳酸酐酶能减少碳酸氢盐分泌，进而减少眼房水的分泌，降低眼内压。
6. 原文标题及出处：
Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors To Explore a MEK Resistance Hypothesis
J. Med. Chem., 2015, 58 (6), pp 2834–2844
DOI: 10.1021/acs.jmedchem.5b00098
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：Dyrk1B激酶抑制剂
摘要原文：
Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response.
备注：
Dyrk1B也叫Mirk或Minibrain相关激酶，是一个双特异性的丝苏氨酸激酶，介导骨骼肌的存活和分化。Dyrk1B在多种肿瘤中表达，在维持细胞静息中发挥重要作用。
(by 浮米网)
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