title: Discovery of SOAT2 inhibitors from synthetic small molecules.
abstract: Synthesis of new functionalized molecules and identification of biofunctional molecules can lead to the development of therapeutic leads and molecular tools for biomedical research. We have recently reported oxa-hetero-Diels-Alder reactions of enones with isatins to provide functionalized spirooxindole tetrahydropyran derivatives. Twenty-one compounds from the spirooxindole tetrahydropyran derivatives and related molecules were screened for inhibition of sterol O-acyltransferase (SOAT) isozymes SOAT1 and SOAT2. Three racemic derivatives inhibited the SOAT2 isozyme with three-fold or better selectivity for SOAT2 than for SOAT1. The enantiomerically enriched forms of the most efficient racemic inhibitor of SOAT2 were further evaluated; one enantiomer inhibited SOAT2 with an IC50of 1.5μM and was 10-fold more selective for SOAT2 than SOAT1.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Ohshiro
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: tomodah@pharm.kitasato-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
authors.affiliation: Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan.
authors.forename: Feng
authors.initials: F
authors.lastname: Yin
authors.affiliation: Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan.
authors.forename: Hai-Lei
authors.initials: HL
authors.lastname: Cui
authors.affiliation: Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan.
authors.forename: Pandurang V
authors.initials: PV
authors.lastname: Chouthaiwale
authors.affiliation: Chemistry and Chemical Bioengineering Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan. Electronic address: ftanaka@oist.jp.
authors.forename: Fujie
authors.initials: F
authors.lastname: Tanaka
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097587:Sterol O-Acyltransferase 2
chemical_list: D004791:Enzyme Inhibitors; D011714:Pyrans; D054852:Small Molecule Libraries; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C493492:sterol O-acyltransferase 1
keywords: Hetero-Diels-Alder reaction; Inhibitor; Isozyme; Spirooxindole; Sterol O-acyltransferase; Tetrahydropyran