論文

査読有り 国際誌
2015年5月14日

Discovery of a Novel Series of N-Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase-2 Inhibitors.

Journal of medicinal chemistry
  • Kenjiro Sato
  • Hiroki Takahagi
  • Takeshi Yoshikawa
  • Shinji Morimoto
  • Takafumi Takai
  • Kousuke Hidaka
  • Masahiro Kamaura
  • Osamu Kubo
  • Ryutaro Adachi
  • Tsuyoshi Ishii
  • Toshiyuki Maki
  • Taisuke Mochida
  • Shiro Takekawa
  • Masanori Nakakariya
  • Nobuyuki Amano
  • Tomoyuki Kitazaki
  • 全て表示

58
9
開始ページ
3892
終了ページ
909
記述言語
英語
掲載種別
DOI
10.1021/acs.jmedchem.5b00178

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from N-phenylbenzenesulfonamide derivative 1 with moderate potency for MGAT2 inhibition, we explored an effective location of the hydrophobic group at the 1-position to enhance MGAT2 inhibitory activity. Shifting the hydrophobic group to the adjacent position followed by introduction of a bicyclic central core to restrict the substituent orientation produced N-phenylindoline-5-sulfonamide derivative 10b, which displayed much improved potency, with an IC50 value of 1.0 nM. This compound also exhibited excellent selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1). Subsequent optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indole-1-carboxamide (24d) endowed with potent MGAT2 inhibitory activity (IC50 = 3.4 nM) and high oral bioavailability (F = 52%, mouse). In a mouse oral fat tolerance test, oral administration of this compound effectively suppressed the elevation of plasma triacylglycerol levels.

リンク情報
DOI
https://doi.org/10.1021/acs.jmedchem.5b00178
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/25897973
ID情報
  • DOI : 10.1021/acs.jmedchem.5b00178
  • PubMed ID : 25897973

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