Literature DB >> 24900587

Discovery of DF-461, a Potent Squalene Synthase Inhibitor.

Masanori Ichikawa1, Masami Ohtsuka1, Hitoshi Ohki1, Masahiro Ota1, Noriyasu Haginoya1, Masao Itoh1, Yoshihiro Shibata1, Yutaka Ishigai1, Koji Terayama, Akira Kanda1, Kazuyuki Sugita1, Hiroyuki Usui1.   

Abstract

We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.

Entities:  

Keywords:  Squalene synthase; dyslipidemia; inhibitor; triazolobenzoxazepine

Year:  2013        PMID： 24900587      PMCID： PMC4027440          DOI： 10.1021/ml400151c

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  20 in total

1.  Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.

Authors:  Jeffrey A Pfefferkorn; John Litchfield; Richard Hutchings; Xue-Min Cheng; Scott D Larsen; Bruce Auerbach; Mark R Bush; Chitase Lee; Noe Erasga; Daniel M Bowles; David C Boyles; Gina Lu; Catherine Sekerke; Valerie Askew; Jeffrey C Hanselman; Lisa Dillon; Zhiwu Lin; Andrew Robertson; Karl Olsen; Carine Boustany; Karen Atkinson; Theunis C Goosen; Vaishali Sahasrabudhe; Jonathan Chupka; David B Duignan; Bo Feng; Renato Scialis; Emi Kimoto; Yi-An Bi; Yurong Lai; Ayman El-Kattan; Rebecca Bakker-Arkema; Paul Barclay; Erick Kindt; Vu Le; Jaap W Mandema; Mark Milad; Bradley D Tait; Robert Kennedy; Bharat K Trivedi; Mark Kowala
Journal:  Bioorg Med Chem Lett       Date:  2010-11-26       Impact factor: 2.823

2.  Isopentenoid synthesis in isolated embryonic Drosophila cells. Farnesol catabolism and omega-oxidation.

Authors:  D Gonzalez-Pacanowska; B Arison; C M Havel; J A Watson
Journal:  J Biol Chem       Date:  1988-01-25       Impact factor: 5.157

Review 3.  Management of primary hyperlipidemia.

Authors:  R J Havel; E Rapaport
Journal:  N Engl J Med       Date:  1995-06-01       Impact factor: 91.245

4.  Discovery of a new 2-aminobenzhydrol template for highly potent squalene synthase inhibitors.

Authors:  Masanori Ichikawa; Aki Yokomizo; Masao Itoh; Hiroyuki Usui; Hironari Shimizu; Makoto Suzuki; Koji Terayama; Akira Kanda; Kazuyuki Sugita
Journal:  Bioorg Med Chem       Date:  2011-02-03       Impact factor: 3.641

5.  Synthesis and activity of a novel series of 3-biarylquinuclidine squalene synthase inhibitors.

Authors:  G R Brown; D S Clarke; A J Foubister; S Freeman; P J Harrison; M C Johnson; K B Mallion; J McCormick; F McTaggart; A C Reid; G J Smith; M J Taylor
Journal:  J Med Chem       Date:  1996-07-19       Impact factor: 7.446

6.  Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid A or with farnesol.

Authors:  R G Bostedor; J D Karkas; B H Arison; V S Bansal; S Vaidya; J I Germershausen; M M Kurtz; J D Bergstrom
Journal:  J Biol Chem       Date:  1997-04-04       Impact factor: 5.157

7.  Synthesis and biological evaluation of novel propylamine derivatives as orally active squalene synthase inhibitors.

Authors:  Tsukasa Ishihara; Hirotoshi Kakuta; Hiroshi Moritani; Tohru Ugawa; Isao Yanagisawa
Journal:  Bioorg Med Chem       Date:  2004-11-15       Impact factor: 3.641

Review 8.  Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors.

Authors:  Jonathan A Tobert
Journal:  Nat Rev Drug Discov       Date:  2003-07       Impact factor: 84.694

9.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.

Authors:  J Shepherd; S M Cobbe; I Ford; C G Isles; A R Lorimer; P W MacFarlane; J H McKillop; C J Packard
Journal:  N Engl J Med       Date:  1995-11-16       Impact factor: 91.245

10.  Withdrawal of cerivastatin from the world market.

Authors:  Curt D Furberg; Bertram Pitt
Journal:  Curr Control Trials Cardiovasc Med       Date:  2001
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  4 in total

1.  Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes.

Authors:  Elizabeth A Rondini; Zofia Duniec-Dmuchowski; Daniela Cukovic; Alan A Dombkowski; Thomas A Kocarek
Journal:  J Pharmacol Exp Ther       Date:  2016-05-25       Impact factor: 4.030

2.  A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor.

Authors:  Alastair G Kerr; Lawrence C S Tam; Ashley B Hale; Milena Cioroch; Gillian Douglas; Sarina Agkatsev; Olivia Hibbitt; Joseph Mason; James Holt-Martyn; Carole J R Bataille; Graham M Wynne; Keith M Channon; Angela J Russell; Richard Wade-Martins
Journal:  J Pharmacol Exp Ther       Date:  2017-03-30       Impact factor: 4.030

Review 3.  Human isoprenoid synthase enzymes as therapeutic targets.

Authors:  Jaeok Park; Alexios N Matralis; Albert M Berghuis; Youla S Tsantrizos
Journal:  Front Chem       Date:  2014-07-22       Impact factor: 5.221

4.  Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect.

Authors:  Yankun Chen; Xi Chen; Ganggang Luo; Xu Zhang; Fang Lu; Liansheng Qiao; Wenjing He; Gongyu Li; Yanling Zhang
Journal:  Molecules       Date:  2018-04-28       Impact factor: 4.411
  4 in total

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