Ileal bile acid transporter IBAT and apical sodiumcodependent bile acid transporter ASBT inhibitors

As an alternative to cholesterol absorption inhibitors, specific inhibitors of the IBAT, also known as the apical co-dependent bile acid transporter are being sought. The IBAT system facilitates the reuptake of bile acids from the intestine, thus conserving the sterol pool. Functionally, an IBAT inhibitor should produce the same physiological effects of LDLc lowering achieved by anionic resins, such as cholestyramine, which sequester bile acids in the gut, without the high grams per day doses that dramatically limit patient compliance with sequesterants. The first entrant in this field, 34 (S-8921; Figure 14), has demonstrated oral efficacy in lowering LDLc with no accompanying change in HDLc at doses as low as 1 mgkg~ 1 day_ 1.78 Development of 34 has been discontinued as it showed no clinical benefit over existing products.

The benzothiazepine IBAT inhibitor, 264W94 35 (IC50 = 0.25 mM),79 dose-dependently (0.03-1.0 mgkg"1 day" 1 p.o. b.i.d.) reduced VLDLc and LDLc by up to 60% in diet-induced hypercholesterolemic rats, in only 3.5 days. Although it entered the clinic, its development has been discontinued. Despite these initial discouraging results, the opportunity exists to provide significant lipid lowering with IBAT inhibitors, either alone or in combination with a statin. In addition, a nonabsorbed version of an apical co-dependent bile acid transporter inhibitor based on a chiral poly-substituted benzothiepine core would have the advantage of delivering the inhibitor to the site of action with fewer accompanying side effects due to systemic exposure. Compounds 36 (IC50 = 0.28 nM) and 37 (IC50 = 0.75 nM) are potent apical co-dependent bile acid transporter inhibitors, which had no significant systemic exposure in rats but lowered LDLc upon oral dosing. The quaternary ammonium groups in 36 and 37 (Figure 14) also satisfied important solid-state criteria of nonhygroscopicity and crystallinity to advance in preclinical testing.80

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