Muise Eric S, Zhu Yonghua, Verras Andreas, Karanam Bindhu V, Gorski Judith, Weingarth Drew, Lin Hua V, Hwa Joyce, Thompson John R, Hu Guanghui, Liu Jian, He Shuwen, DeVita Robert J, Shen Dong-Ming, Pinto Shirly
Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
PLoS One. 2014 Feb 18;9(2):e88908. doi: 10.1371/journal.pone.0088908. eCollection 2014.
Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.
抑制二酰甘油O-酰基转移酶1（DGAT1）一直是代谢紊乱研究中备受关注的一种机制。DGAT1抑制已被证明是一系列代谢途径中的关键调节因子；然而，基于DGAT1基因敲除小鼠的表型，预计DGAT1的药理抑制可能会导致皮肤相关的不良反应。开发针对关键代谢组织的小分子DGAT1抑制剂的目标之一是避免对皮肤局部的DGAT1酶产生活性。在本报告中，我们描述了一种基于模型的方法，以识别具有导致不同暴露分布的物理性质的分子。此外，我们展示了基于组织学和RNA的生物标志物方法，这些方法可以在临床前检测皮脂腺萎缩，可作为临床环境中的潜在生物标志物。
