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.

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

“…Similarly, several specific ASBT inhibitors were able to significantly lower plasma cholesterol levels and/or prevent atherosclerosis in animal studies, supporting the feasibility of a cholesterol-lowering therapy by blocking the ASBT transport function Higaki et al 1998;Ichihashi et al 1998;West et al 2002;Li et al 2004;Tremont et al 2005). Several classes of ASBT inhibitors were developed (see Fig.…”

“…This compound competitively inhibited ASBT with K i of 0.2 μM and was a ∼500-fold more potent inhibitor than 2164U90 of the ileal bile acid absorption in rats in vivo (Root et al 2002). More recently, large series of benzothiepine derivatives 4 were synthesised and several compounds of this group potently inhibit Asbt with IC 50 values in the low nanomolar range Tremont et al 2005). One reagent of this group, SC-435 5 , was identified as a potent and nonabsorbed inhibitor of ASBT (IC 50 =1.5 nM).…”

Intestinal transport and metabolism of bile acids

“…A major role for the ASBT in intestinal bile acid absorption is supported by genetic evidence, where targeted inactivation of the ASBT eliminates enterohepatic cycling of bile acids in mice ( 17, 60, 61 ) and ASBT loss-of-function mutations in humans are associated with intestinal bile acid malabsorption ( 16 ), and by pharmacological evidence where administration of small molecule inhibitors of the ASBT to animal models reduced intestinal bile acid absorption (62)(63)(64). Although this review focuses on the intestine, it should be noted that other epithelia, including renal proximal tubule cells, cholangiocytes lining the biliary tract, and gallbladder epithelial cells, also express the ASBT ( 39,(65)(66)(67).…”

Bile acids: Trying to understand their chemistry and biology with the hope of helping patients

“…of the ileal apical transporter was developed by Monsanto-Searle, 64 but has been shelved by Pfizer who took over Monsanto-Searle, presumably because the market for such an agent is tiny.…”