Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 1).

Abstract

Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14 cells. A 3R,4R,5R/3S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.

• Authors: Samuel J Tremont, Len F Lee, Horng-Chih Huang, Bradley T Keller, Shyamal C Banerjee, Scott R Both, Andrew J Carpenter, Ching-Cheng Wang, Danny J Garland, Wei Huang, Claude Jones, Kevin J Koeller, Steve A Kolodziej, James Li, Robert E Manning, Matthew W Mahoney, Raymond E Miller, Deborah A Mischke, Nigam P Rath, Theresa Fletcher, Emily J Reinhard, Michael B Tollefson, William F Vernier, Grace M Wagner, Steve R Rapp, Judy Beaudry, Kevin Glenn, Karen Regina, Joe R Schuh, Mark E Smith, Jay S Trivedi, David B Reitz
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 48 Issue 18 Pg. 5837-52 (Sep 08 2005) ISSN: 0022-2623 [Print] United States
• PMID: 16134950 (Publication Type: Journal Article)

Chemical References

• Anticholesteremic Agents
• Benzothiepins
• Bile Acids and Salts
• Organic Anion Transporters, Sodium-Dependent
• Symporters
• sodium-bile acid cotransporter
• Taurocholic Acid

Topics

• Animals
• Anticholesteremic Agents (chemical synthesis, chemistry, pharmacology)
• Benzothiepins (chemical synthesis, chemistry, pharmacology)
• Bile Acids and Salts (metabolism)
• Biological Availability
• Cell Line
• Cricetinae
• Crystallography, X-Ray
• Humans
• Magnetic Resonance Spectroscopy
• Male
• Mesocricetus
• Organic Anion Transporters, Sodium-Dependent (antagonists & inhibitors)
• Rats
• Stereoisomerism
• Structure-Activity Relationship
• Symporters (antagonists & inhibitors)
• Taurocholic Acid (metabolism)