title: Identification and characterization of sebaceous gland atrophy-sparing DGAT1 inhibitors.
abstract: 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.
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Muise
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Bindhu V
authors.initials: BV
authors.lastname: Karanam
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Judith
authors.initials: J
authors.lastname: Gorski
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Drew
authors.initials: D
authors.lastname: Weingarth
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Hua V
authors.initials: HV
authors.lastname: Lin
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Joyce
authors.initials: J
authors.lastname: Hwa
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Hu
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Whithouse Station, New Jersey, United States of America.
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
mesh_terms: D000818:Animals; D001284:Atrophy / Q000139:chemically induced / Q000201:enzymology; D015415:Biomarkers / Q000378:metabolism; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D012627:Sebaceous Glands / Q000187:drug effects* / Q000473:pathology*; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D054852:Small Molecule Libraries / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D051048:Diacylglycerol O-Acyltransferase