title: Synthesis and evaluation of diarylthiazole derivatives that inhibit activation of sterol regulatory element-binding proteins.
abstract: Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives. Our structure-activity relationships led to the identification of N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide (24, FGH10019) as the most potent druglike molecule among the analogues tested. Compound 24 has high aqueous solubility and membrane permeability and may serve as a seed molecule for further development.
authors.affiliation: Institute for Chemical Research, Kyoto University, Uji, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kamisuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Shirakawa
authors.forename: Akira
authors.initials: A
authors.lastname: Kugimiya
authors.forename: Lutfi
authors.initials: L
authors.lastname: Abu-Elheiga
authors.forename: Hea-Young Park
authors.initials: HY
authors.lastname: Choo
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamada
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimogawa
authors.forename: Salih J
authors.initials: SJ
authors.lastname: Wakil
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004435:Eating / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D008297:Male; D008567:Membranes, Artificial; D051379:Mice; D008820:Mice, Obese; D010539:Permeability; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D051779:Sterol Regulatory Element Binding Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D008567:Membranes, Artificial; C561240:N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide; D011725:Pyridines; D051779:Sterol Regulatory Element Binding Proteins; D013449:Sulfonamides; D013844:Thiazoles; C545733:fatostatin