Arylsulfonylamino-Benzanilides as Inhibitors of the Apical Sodium-Dependent Bile Salt Transporter (SLC10A2)

Abstract

Abstract:The apical sodium-dependent bile salt transporter (ASBT) plays a pivotal role in maintaining bile acid homeostasis. Inhibition of ASBT would reduce bile acid pool size and lower cholesterol levels. In this report, a series of novel arylsulfonylaminobenzanilides were designed and synthesized as potential inhibitors of ASBT. Most of them demonstrated great potency against ASBT's bile acid transport activity. In particular, compound 5g 2 inhibited ASBT activity with an IC 50 value of 0.11 μM. These compounds represent potential cholesterol-lowering drugs.

A novel ASBT inhibitor, IMB17-15, repressed nonalcoholic fatty liver disease development in high-fat diet-fed Syrian golden hamsters

“…As demonstrated in previous studies [11], IMB17-15 is a novel and potent ASBT inhibitor. Consistent with the results of other ASBT inhibitor-related studies [9], our results showed that IMB17-15 increased the blood and hepatic BA levels and impaired the ileal BA absorption.…”

“…Recently, we synthesized a series of novel potent ASBT inhibitors using cell-based in vitro assays [11], including N-(3,4dichlorophenyl)−2-(3-trifluoromethoxy) benzamide, which is also referred to as IMB17-15 ( Fig. 1a).…”

A novel class of apical sodium--dependent bile salt transporter inhibitors: 1-(2,4-bifluorophenyl)-7-dialkylamino-1,8-naphthyridine-3-carboxamides

“…HEK293T cells were seeded in 12-well plates and transiently transfected with 0.5 μg/well pcDNA3.1/ASBT or the negative control plasmid pcDNA3.1 using lipofactamine 2000 (Invitrogen, Carlsbad, CA, USA) according to the manufacturer׳s instructions. Twenty-four hours after transfection, HEK293T cells were assayed for taurocholic acid uptake as previously described with minor modifications 16 . Briefly, cells were washed twice with warm wash and uptake buffer (116 mmol/L NaCl, 5.3 mmol/L KCl, 1.1 mmol/L KH 2 PO 4 , 0.8 mmol/L MgSO 4 , 1.8 mmol/L CaCl 2 , 11 mmol/L d -dextrose/ d -glucose, and 10 mmol/L HEPES, pH 7.4), and then incubated with the same buffer containing the indicated concentrations of test compounds (dissolved in dimethyl sulfoxide) and 1 μCi/mL of [ 3 H]-taurocholic acid (TCA, 0.2 μmol/L) (PerkinElmer Life Sciences) for 10 min.…”

“…Our laboratory has been dedicated to the investigation and development of ASBT inhibitors and has obtained a series of compounds with good activity 16 . NC-1, a compound obtained by extensive screening in our lab, was found to have potent ASBT inhibitory activity.…”

Anthranilic amide and imidazobenzothiadiazole compounds disruptMycobacterium tuberculosismembrane potential

“…The first of these series is built upon on anthranilic amide core. The anthranilic amide scaffold has found use in small molecules targeted at a range of therapeutic applications: management of chronic pain 14 – 16 and inflammation, 17 reduction of cholesterol levels, 18 , 19 inhibition of hepatitis C, 20 and anticancer therapeutics. 21 , 22 Peukert et al identified a series of anthranilic amide-based Kv1.5 channel blockers with moderate oral bioavailability and no significant hERG inhibition.…”