title: Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis.
abstract: Modification of the carboxyl group at the 3-position and introduction of protective groups to the hydroxy group of the 4,1-benzoxazepine derivative 2 (metabolite of 1) were carried out, and the inhibitory activity for squalene synthase and cholesterol synthesis in the liver was investigated. Among these compounds, the glycine derivative 3a and beta-alanine derivative 3f exhibited the most potent inhibition of squalene synthase prepared from HepG2 cells (IC(50) = 15 nM). On the other hand, the piperidine-4-acetic acid derivative 4a, which was prepared by acetylation of 3j, was the most effective inhibitor of cholesterol synthesis in rat liver (ED(50) = 2.9 mg/kg, po). After oral administration, 4a was absorbed and rapidly hydrolyzed to deacylated 3j. Compound 3j was detected mainly in the liver, but the plasma level of 3j was found to be low. Compounds 3j and 4a were found to be competitive inhibitors with respect to farnesyl pyrophosphate. Further evaluation of 4a as a cholesterol-lowering and antiatherosclerotic agent is underway.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Juso-Honmachi, Yodogawa-ku, Osaka 532-8686, Japan, and Strategic Product Planning Department, Takeda Chemical Industries, Ltd., 4-1-1, Doshomachi, Chuo-ku, Osaka 540-8645, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.forename: Ryu-ichi
authors.initials: R
authors.lastname: Tozawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishimoto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Koichiro
authors.initials: K
authors.lastname: Teshima
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Yukimasa
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes; D013329:Structure-Activity Relationship
chemical_list: C466644:1-((1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)acetyl)piperidine-4-acetic acid; D000924:Anticholesteremic Agents; D001381:Azepines; D004791:Enzyme Inhibitors; D010077:Oxazepines; D010880:Piperidines; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C004808:farnesyl pyrophosphate; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase