Meng Charles Q, Ni Liming, Worsencroft Kimberly J, Ye Zhihong, Weingarten M David, Simpson Jacob E, Skudlarek Jason W, Marino Elaine M, Suen Ki-Ling, Kunsch Charles, Souder Amy, Howard Randy B, Sundell Cynthia L, Wasserman Martin A, Sikorski James A
AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, Georgia 30004, USA.
J Med Chem. 2007 Mar 22;50(6):1304-15. doi: 10.1021/jm0614230. Epub 2007 Feb 27.
Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion molecule-1 (VCAM-1) expression. Correlations between lipophilicity determined by calculated logP values and inhibitory efficacy were observed among structurally similar compounds of the series. Various substituents were found to be tolerated at several positions of the chalcone backbone as long as the compounds fell into the right range of lipophilicity. The chalcone alpha,beta-unsaturated ketone moiety seemed to be the pharmacophore required for inhibition of VCAM-1 expression. Compound 19 showed significant antiinflammatory effects in a mouse model of allergic inflammation, indicating that this series of compounds might have therapeutic value for human asthma and other inflammatory disorders.
从一个简单的查尔酮模板出发，通过构效关系（SAR）研究得到了一系列羧基化、杂芳基取代的查尔酮衍生物，它们是血管细胞黏附分子-1（VCAM-1）表达的新型强效抑制剂。在该系列结构相似的化合物中，观察到由计算得到的logP值所确定的亲脂性与抑制效力之间的相关性。只要化合物的亲脂性处于合适范围，查尔酮主链的几个位置上都能耐受各种取代基。查尔酮的α,β-不饱和酮部分似乎是抑制VCAM-1表达所需的药效基团。化合物19在过敏性炎症小鼠模型中显示出显著的抗炎作用，表明该系列化合物可能对人类哮喘和其他炎症性疾病具有治疗价值。
