Identification and Characterization of Sebaceous Gland Atrophy-Sparing DGAT1 Inhibitors

• Published in: PloS one Vol. 9; no. 2; p. e88908
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.02.2014; Public Library of Science (PLoS)
• Subjects: Animals; Atrophy; Atrophy - chemically induced; Atrophy - enzymology; Biology; Biomarkers; Biomarkers - metabolism; Biosynthesis; Chemistry; Diabetes; Diacylglycerol; Diacylglycerol O-acyltransferase; Diacylglycerol O-Acyltransferase - antagonists & inhibitors; Diglycerides; Drug Discovery; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Hydrophobic and Hydrophilic Interactions; Inhibition; Inhibitors; Laboratories; Lipids; Male; Medicine; Metabolic disorders; Metabolic pathways; Metabolism; Mice; Obesity; Peptides; Pharmaceutical industry; Pharmacology; Physical properties; R&D; Research & development; Ribonucleic acid; RNA; Rodents; Sebaceous gland; Sebaceous Glands - drug effects; Sebaceous Glands - pathology; Skin; Skin - drug effects; Skin - enzymology; Skin - metabolism; Small Molecule Libraries - adverse effects; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacology; Tissues; Vaccines; United States > US; New Jersey
• DOI: 10.1371/journal.pone.0088908
• ISSN: 1932-6203

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.