Novel non-systemic inhibitor of ileal apical Na+-dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys

Kitayama, Ken; Nakai, Daisuke; Kono, Keita; Hoop, A. Gerritsen van der; Kurata, Hitoshi; Wit, Elly C. de; Cohen, Louis; Inaba, Tomohiro; Kohama, Takafumi

doi:10.1016/j.ejphar.2006.04.005

Cited by 33 publications

(27 citation statements)

References 42 publications

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“…So far, a number of ASBT inhibitors having various structural characteristics have been synthesized. Among of them, three candidates-264W94, SC-435 and R-146224 ( Figure 1) were reported to block bile acid re-absorption and reduce cholesterol levels significantly in animal models [14][15][16]. In addition, it has recently been demonstrated in a Phase Ⅲ trial that A3309 (Figure 1), another ASBT inhibitor, can be used to treat patients with chronic idiopathic constipation (CIC).…”

Section: Introductionmentioning

confidence: 99%

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

Liu

Xiu-juan

et al. 2013

Molecules

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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.

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Section: Introductionmentioning

confidence: 99%

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

Liu

Xiu-juan

et al. 2013

Molecules

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“…Current therapy of inhibiting bile acid absorption is based on sequestering them by using resins such as cholestyramine and colesevelam that bind bile acids in the intestinal lumen and prevent their absorption (33,34). However, poor patient compliance for cholestyramine and the need of high doses (several g/day) of bile acid sequestrants warrant the need for better and more efficient inhibitors of bile acid absorption (3,22). Therefore, further investigations are needed to delineate the modulation of bile acid absorption in diabetes mellitus at the molecular level.…”

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confidence: 99%

Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

Annaba

Kumar

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin. Am J Physiol Gastrointest Liver Physiol 299: G898 -G906, 2010. First published July 22, 2010; doi:10.1152/ajpgi.00139.2010.-Increased intestinal bile acid absorption and expansion of the bile acid pool has been implicated in the hypercholesterolemia associated with diabetes mellitus. However, the molecular basis of the increase in bile acid absorption in diabetes mellitus is not fully understood. The ileal apical Na ϩ -dependent bile acid transporter (ASBT) is primarily responsible for active reabsorption of the majority of bile acids. Current studies were designed to investigate the modulation of ASBT function and expression in streptozotocin (STZ)-induced diabetes mellitus in rats and to examine the effect of insulin on rat ASBT promoter by insulin. Diabetes mellitus was induced in Sprague-Dawley rats by intraperitoneal injection of low doses of STZ (20 mg/kg body wt) on five consecutive days. Human insulin (10 U/day) was given to a group of diabetic rats for 3 days before euthanasia. RNA and protein were extracted from mucosa isolated from the small intestine and ASBT expression was assessed by real-time quantitative RT-PCR and Western blotting. Our data showed that ASBT mRNA and protein expression were significantly elevated in diabetic rats. Insulin treatment of diabetic rats reversed the increase in ASBT protein expression to control levels. Consistently, ileal Na ϩ -dependent [ 3 H]taurocholic uptake in isolated intestinal epithelial cells was significantly increased in diabetic rats. In vitro studies utilizing intestinal epithelial Caco-2 cells demonstrated that ASBT expression and promoter activity were significantly decreased by insulin. These studies demonstrated that insulin directly influences ASBT expression and promoter activity and that ASBT function and expression are increased in rats with STZinduced diabetes mellitus. The increase in ASBT expression may contribute to disturbances in cholesterol homeostasis associated with diabetes mellitus. hypercholesterolemia; insulinopenia; enterohepatic circulation DIABETES MELLITUS IS A COMPLEX disorder resulting from insulin imbalance and characterized by dyslipidemia and hypercholesterolemia (18,34

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“…Once internalized, reclaimed bile acids are secreted into portal circulation via OST␣-OST␤ for return to the liver via the hepatic bile acid transporter, NTCP (1-3), thereby completing one cycle of enterohepatic circulation (4). Clinically, the intimate link between ASBT and cholesterol may be exploited via blockage of bile acid reuptake, resulting in reduced cholesterol levels (5)(6)(7)(8)(9); this establishes the pharmaceutical relevance of ASBT in treatment of hypercholesterolemia (1, 10 -14). Moreover, ASBT constitutes an attractive target for prodrug strategies aimed at increasing oral bioavailability of poorly absorbed drugs (15)(16)(17).…”

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confidence: 99%

Conserved Aspartic Acid Residues Lining the Extracellular Loop I of Sodium-coupled Bile Acid Transporter ASBT Interact with Na+ and 7α-OH Moieties on the Ligand Cholestane Skeleton

Hussainzada

Silva

Zhang³

et al. 2008

Journal of Biological Chemistry

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Functional contributions of residues Val-99 -Ser-126 lining extracellular loop (EL) 1 of the apical sodium-dependent bile acid transporter were determined via cysteine-scanning mutagenesis, thiol modification, and in silico interpretation. Despite membrane expression for all but three constructs (S112C, Y117C, S126C), most EL1 mutants (64%) were inactivated by cysteine mutation, suggesting a functional role during sodium/bile acid co-transport. A negative charge at conserved residues Asp-120 and Asp-122 is required for transport function, whereas neutralization of charge at Asp-124 yields a functionally active transporter. D124A exerts low affinity for common bile acids except deoxycholic acid, which uniquely lacks a 7␣-hydroxyl (OH) group. Overall, we conclude that (i) Asp-122 functions as a Na ؉ sensor, binding one of two co-transported Na ؉ ions, (ii) Asp-124 interacts with 7␣-OH groups of bile acids, and (iii) apolar EL1 residues map to hydrophobic ligand pharmacophore features. Based on these data, we propose a comprehensive mechanistic model involving dynamic salt bridge pairs and hydrogen bonding involving multiple residues to describe sodium-dependent bile acid transporter-mediated bile acid and cation translocation.

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Novel non-systemic inhibitor of ileal apical Na+-dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys

Cited by 33 publications

References 42 publications

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

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

Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

Conserved Aspartic Acid Residues Lining the Extracellular Loop I of Sodium-coupled Bile Acid Transporter ASBT Interact with Na+ and 7α-OH Moieties on the Ligand Cholestane Skeleton

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Novel non-systemic inhibitor of ileal apical Na+-dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys

Cited by 33 publications

References 42 publications

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

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

Ileal apical Na+-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

Conserved Aspartic Acid Residues Lining the Extracellular Loop I of Sodium-coupled Bile Acid Transporter ASBT Interact with Na+ and 7α-OH Moieties on the Ligand Cholestane Skeleton

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Ileal apical Na⁺-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin