【行业】浮米每周文献快讯：2014年8月（一）

【行业】浮米每周文献快讯：2014年8月（一）2014-08-04 浮米hfoom
上周共有5篇文献。1、阿斯利康的拓扑异构酶II抑制剂AZD5099；2、武田的九肽KISS1受体激动剂；3、阿斯利康的胃饥饿素受体GHS-R1a反向激动剂，被认为是治疗II型糖尿病和肥胖的药物；4、BMS的P2Y1拮抗剂；5、BMS的糖皮质激素受体激动剂1. 原文标题及出处：

Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)

J. Med. Chem., 2014, 57 (14), pp 6060–6082

DOI: 10.1021/jm500462x

公司/组织：阿斯利康

候选药物化学结构式/活性：

                               
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靶点/作用机制：拓扑异构酶II抑制剂

摘要原文：

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

备注：

由于耐药性的存在，需要新型的抗菌药。

一些ATP竞争性细菌拓扑异构酶抑制剂：

                               
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2. 原文标题及出处：

Physicochemically and Pharmacokinetically Stable Nonapeptide KISS1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity

J. Med. Chem., 2014, 57 (14), pp 6105–6115

DOI: 10.1021/jm5005489

公司/组织：武田药品工业

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靶点/作用机制：九肽KISS1受体激动剂

摘要原文：

Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases.

备注：

KISS1受体是孤儿G蛋白偶联受体。KISS1R的配体包括许多神经多肽，例如RFamide和RWamide家族。

3. 原文标题及出处：

Identification, Optimization, and Pharmacology of Acylurea GHS-R1a Inverse Agonists

J. Med. Chem., 2014, 57 (14), pp 6128–6140

DOI: 10.1021/jm500610n

公司/组织：阿斯利康

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靶点/作用机制：胃饥饿素受体GHS-R1a反向激动剂

摘要原文：

Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure–activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.

备注：

外周和中枢神经系统渗透性胃激素受体拮抗剂被认为是治疗II型糖尿病和肥胖的药物。

4. 原文标题及出处：

Discovery of 4-Aryl-7-Hydroxyindoline-Based P2Y1 Antagonists as Novel Antiplatelet Agents

J. Med. Chem., 2014, 57 (14), pp 6150–6164

DOI: 10.1021/jm5006226

公司/组织：BMS

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靶点/作用机制：P2Y1拮抗剂

摘要原文：

Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y12 and P2Y1. Blocking P2Y12 receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y12 inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y1 antagonist, 1. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y12 antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y1 antagonism as a promising new antiplatelet target.

备注：

ADP激活血小板通路是通过血小板表面的两个GPCR: P2Y12,偶联Gi2Y1,偶联Gq.

5. 原文标题及出处：

Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonists

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3268–3273

DOI: 10.1016/j.bmcl.2014.06.010

公司/组织：BMS

候选药物化学结构式/活性：

                               
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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：

(by 浮米网)