title: Discovery of novel benzoxazinones as potent and orally active long chain fatty acid elongase 6 inhibitors.
abstract: A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.
authors.affiliation: Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan. miztnitk@gmail.com
authors.forename: Takashi
authors.initials: T
authors.lastname: Mizutani
authors.forename: Shiho
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nagase
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimura
authors.forename: Takahide
authors.initials: T
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Nagumo
authors.forename: Ken
authors.initials: K
authors.lastname: Shimamura
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Kitazawa
authors.forename: Maki
authors.initials: M
authors.lastname: Kanesaka
authors.forename: Ryo
authors.initials: R
authors.lastname: Yoshimoto
authors.forename: Katsumi
authors.initials: K
authors.lastname: Aragane
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D048588:Benzoxazines / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D048588:Benzoxazines; C000630953:ELOVL3 protein, human; C000630955:ELOVL6 protein, human; C000630960:Elovl3 protein, mouse; C000630968:Elovl6 protein, mouse; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases