浮米每周文献快讯：2014年9月（三）

                                                                 浮米每周文献快讯：2014年9月（三）                                                            作者：浮米网 来源：浮米网 2014-09-18

1. 原文标题及出处：N-[6-(4-Butanoyl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl]-5-chloro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-indole-3-carboxamide (SAR216471), a Novel Intravenous and Oral, Reversible, and Directly Acting P2Y12 Antagonist

J. Med. Chem., 2014, 57 (17), pp 7293–7316

DOI: 10.1021/jm500588w

公司/组织：赛诺菲

候选药物化学结构式/活性：

                               
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靶点/作用机制：P2Y12拮抗剂

摘要原文：

In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.

备注：

受伤红血细胞或内皮细胞释放的ADP是激活和聚集血小板的关键因子。ADP能结合两个受体： P2Y1 和P2Y12。

2. 原文标题及出处：3-Alkoxy-pyrrolo[1,2-b]pyrazolines as Selective Androgen Receptor Modulators with Ideal Physicochemical Properties for Transdermal Administration

J. Med. Chem., 2014, 57 (17), pp 7396–7411

DOI: 10.1021/jm5009049

公司/组织：诺华

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靶点/作用机制：雄激素受体调节剂

摘要原文：

We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess excellent physicochemical properties for transdermal administration. Compound 26 bound to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activated AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed high aqueous solubility of 1.3 g/L at pH 7.4, and an in silico model as well as a customized parallel artificial membrane permeability assay indicated good skin permeation. Indeed, when measuring skin permeation through excised human skin, an excellent flux of 2 μg/(cm2·h) was determined without any permeation enhancers. In a 2 week Hershberger model using castrated rats, the compound showed dose-dependent effects fully restoring skeletal muscle weight at 0.3 mg/kg/day after subcutaneous administration with high selectivity over prostate stimulation.

备注：

迟发性性腺功能减退症和其他男性性腺机能减退目前常采用不同睾丸素荷尔蒙疗法。而这类疗法的潜在风险可能包括前列腺和心血管疾病。采用选择性雄激素受体调节剂有望于解决这类问题。

3. 原文标题及出处：Discovery of (R)-1-(7-Chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): A Temperature-Neutral Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonist with Analgesic Efficacy

J. Med. Chem., 2014, 57 (17), pp 7412–7424

DOI: 10.1021/jm500916t

公司/组织：AbbVie Inc.

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靶点/作用机制：瞬时受体电位香草酸受体1(TRPV1)拮抗剂

摘要原文：

The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.

备注：

一些选择性TRPV1小分子拮抗剂的发现证实了阻断该受体在炎性、关节炎和神经疼痛的临床前模型中有效。

4. 原文标题及出处：

Discovery of novel non-carboxylic acid 5-amino-4-cyanopyrazole derivatives as potent and highly selective LPA1R antagonists

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4450–4454

DOI: 10.1016/j.bmcl.2014.08.001

公司/组织：罗氏

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靶点/作用机制：LPA1R拮抗剂

摘要原文：

High throughput screening (HTS) of our chemical library identified 3-alkylamino-2-aryl-5H-imidazo[1,2,b]pyrazol-7-carbonitrile 1 as a potent antagonist of the LPA1 receptor (LPA1R). Further evaluation of this class of compounds indicated that LPA1R antagonist activity originated from the degradation of the parent molecule in DMSO during the assay conditions. Here, we describe the isolation and characterization of the degradation products and their LPA1R antagonist activity. We further profiled these novel non-carboxylic acid LPA1R antagonists and demonstrated their inhibition of LPA-induced proliferation and contraction of normal human lung fibroblasts (NHLF).

备注：

溶血磷脂酸类LPA通过作用于LPA受体能刺激细胞增殖、粘附、收缩和迁移，是一个有丝分裂调节剂。

(by 浮米网

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