Document Report Card

ID: ALA1141078

Journal: J Med Chem

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

Authors: Tremont SJ, Lee LF, Huang HC, Keller BT, Banerjee SC, Both SR, Carpenter AJ, Wang CC, Garland DJ, Huang W, Jones C, Koeller KJ, Kolodziej SA, Li J, Manning RE, Mahoney MW, Miller RE, Mischke DA, Rath NP, Fletcher T, Reinhard EJ, Tollefson MB, Vernier WF, Wagner GM, Rapp SR, Beaudry J, Glenn K, Regina K, Schuh JR, Smith ME, Trivedi JS, Reitz DB.

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.

CiteXplore: 16134950

DOI: 10.1021/jm040215+