Inhibitors of acyl-CoA: Cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 13. Design, synthesis and biological evaluation of tetrazole anilides as potent inhibitors of ACAT in vitro and hypocholesterolemic agents in vivo

✍ Scribed by Patrick M. O'Brien; Drago R. Sliskovic; Adele Bernabei; Timothy Hurley; Maureen K. Anderson; Richard F. Bousley; Brian R. Krause; Richard L. Stanfield

• Publisher: Elsevier Science
• Year: 1995
• Tongue: English
• Weight: 274 KB
• Volume: 5
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/0960-894x(95)00025-o

✦ Synopsis

The syntheses and biological activities for anilides derived from 2-phenyl-2-(dodecyl-2H-tetrazol-5-yl)acetic acid are described. Evidence is provided that one of these compounds, (+)-8b, stereoselectively inhibits ACAT in vitro and possesses superior efficacy in vivo compared to (-)-8b or the racemic mixture (+)-8b.

We have recently reported on a series of benzamide and nicotinamide derivatives (1) that potently inhibit ACAT in vitro and are efficacious in lowering plasma total cholesterol in vivo. I Evidence was provided that the (N-dodecyltetrazol-5-yl)-benzyl moiety in I is necessary for potent inhibition, since replacing this functionality with an oleyl side chain or varying the tetrazole chain length, resulted in a marked reduction in inhibitory activity. In a related study however, oleic acid anilides, substituted with electron donating groups on the 2,6-or 2,4,6-aryl positions, potently inhibit ACAT in vitro with ICs0's in the 7 to 700 nM range.2 Since fatty acid anilides have been shown to be significantly more potent than the corresponding benzamide isosteres,l,3 we sought to improve the in vitro activity of the tetrazole derivatives by combining optimal structural features from both series, by replacing the benzamide bond of 1 with 2,6-diisopropyl-and 2,4,6trimethoxy substituted anilide bioisosteres (2). Of the compounds prepared, a trimethoxyphenyl analog of 2 was resolved into individual enantiomers, in order to assess whether the biological activity observed for 2 resided in one particular enantiomeric form. In this paper, we will describe the syntheses and biological results for this novel series of tetrazole amide ACAT inhibitors. Ph O Ph R~NJJ"~ *N (CH2)I1CH 3