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Discovery of Diphenylacetamides as CXCR7 Inhibitors with Novel β-Arrestin Antagonist Activity.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-05-14 , DOI: 10.1021/acsmedchemlett.0c00163 Elnaz Menhaji-Klotz 1 , Jessica Ward 1 , Janice A Brown 2 , Paula M Loria 2 , Carina Tan 1 , Kevin D Hesp 2 , Keith A Riccardi 2 , John Litchfield 1 , Markus Boehm 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-05-14 , DOI: 10.1021/acsmedchemlett.0c00163 Elnaz Menhaji-Klotz 1 , Jessica Ward 1 , Janice A Brown 2 , Paula M Loria 2 , Carina Tan 1 , Kevin D Hesp 2 , Keith A Riccardi 2 , John Litchfield 1 , Markus Boehm 1
Affiliation
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The atypical chemokine receptor CXCR7 has been studied in various disease settings including immunological diseases and heart disease. Efforts to elucidate the role of CXCR7 have been limited by the lack of suitable chemical tools with a range of pharmacological profiles. A high-throughput screen was conducted to discover novel chemical matter with the potential to modulate CXCR7 receptor activity. This led to the identification of a series of diphenylacetamides confirmed in a CXCL12 competition assay indicating receptor binding. Further evaluation of this series revealed a lack of activity in the functional assay measuring β-arrestin recruitment. The most potent representative, compound 10 (Ki = 597 nM), was determined to be an antagonist in the β-arrestin assay (IC50 = 622 nM). To our knowledge, this is the first reported small molecule β-arrestin antagonist for CXCR7, useful as an in vitro chemical tool to elucidate the effects of CXCL12 displacement with β-arrestin antagonism in models for diseases such as cardiac injury and suitable as starting point for hit optimization directed toward an in vivo tool compound for studying CXCR7 receptor pharmacology.
中文翻译：
发现具有新型β-Arrestin拮抗剂活性的CXCR7抑制剂二苯乙酰胺。
非典型趋化因子受体CXCR7已在包括免疫疾病和心脏病在内的各种疾病中得到了研究。缺乏适当的具有多种药理学特征的化学工具限制了阐明CXCR7的作用。进行了高通量筛选，以发现可能调节CXCR7受体活性的新型化学物质。这导致鉴定出一系列在CXCL12竞争试验中证实的表明受体结合的二苯乙酰胺。对该系列的进一步评估显示，在测量β-arrestin募集的功能测定中缺乏活性。最有力的代表化合物10（K i = 597 nM）在β-arrestin分析中被确定为拮抗剂（IC50 = 622 nM）。据我们所知，这是第一个报道的CXCR7小分子β-arrestin拮抗剂，可作为体外化学工具来阐明CXCL12置换与β-arrestin拮抗作用在诸如心脏损伤等疾病模型中的适用性，并作为起点针对用于研究CXCR7受体药理的体内工具化合物的命中优化。
更新日期：2020-05-14
中文翻译：
发现具有新型β-Arrestin拮抗剂活性的CXCR7抑制剂二苯乙酰胺。
非典型趋化因子受体CXCR7已在包括免疫疾病和心脏病在内的各种疾病中得到了研究。缺乏适当的具有多种药理学特征的化学工具限制了阐明CXCR7的作用。进行了高通量筛选，以发现可能调节CXCR7受体活性的新型化学物质。这导致鉴定出一系列在CXCL12竞争试验中证实的表明受体结合的二苯乙酰胺。对该系列的进一步评估显示，在测量β-arrestin募集的功能测定中缺乏活性。最有力的代表化合物10（K i = 597 nM）在β-arrestin分析中被确定为拮抗剂（IC50 = 622 nM）。据我们所知，这是第一个报道的CXCR7小分子β-arrestin拮抗剂，可作为体外化学工具来阐明CXCL12置换与β-arrestin拮抗作用在诸如心脏损伤等疾病模型中的适用性，并作为起点针对用于研究CXCR7受体药理的体内工具化合物的命中优化。
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