Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)

Huang, Hengming; Tremont, Samuel J.; Lee, Len F.; Keller, Bradley T.; Carpenter, Andrew J.; Wang, Ching‐Cheng; Banerjee, Shyamal C.; Both, Scott R; Fletcher, Theresa; Garland, Daniel J.; Huang, Wei; Jones, Claude R.; Koeller, Kevin J.; Kolodziej, Stephen A.; Li, James; Manning, Robert E.; Mahoney, Matthew W.; Miller, Raymond E.; Mischke, Deborah A.; Rath, Nigam P.; Reinhard, Emily J.; Tollefson, Michael B.; Vernier, William F.; Wagner, Grace M; Rapp, Steve; Beaudry, Judy; Glenn, Kevin C.; Regina, Karen J.; Schuh, Joe R.; Smith, Mark E.; Trivedi, Jay; Reitz, David B.

doi:10.1021/jm0402162

Cited by 44 publications

(22 citation statements)

References 13 publications

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“…The Monsanto-Searle group initially developed a new series of 2,3-disubstituted-4-phenylquinolines (similar to the Shinogi ester substituted napthol compounds) and benzothiazepine-based compounds (Tollefson et al 2003) that inhibited the ASBT at micromolar and nanomolar concentrations, respectively. This group later developed on published on a series of potent benzothiepine-based inhibitors, demonstrating their activity as potent competitive inhibitors of the ASBT (Bhat et al 2003; Huang et al 2005; Tremont et al 2005), and characterizing the mechanisms responsible for the LDL-lowering in various animal models (Huff et al 2002; Bhat et al 2003; Telford et al 2003; West et al 2003). The Monsanto-Searle compound entered the clinical trial phase, but does not appear to have progressed further, potentially due to questions over efficacy and dose-related diarrhea (Hofmann and Hagey 2008).…”

Section: Development Of Asbt Inhibitorsmentioning

confidence: 99%

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

Dawson

2010

Handbook of Experimental Pharmacology

188

166

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Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα-OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα-OSTα. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug-drug interactions.

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Section: Development Of Asbt Inhibitorsmentioning

confidence: 99%

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

Dawson

2010

Handbook of Experimental Pharmacology

188

166

View full text Add to dashboard Cite

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“…Because ASBT is localized on the apical membrane of the lumen in the ileum, its inhibitors can block ASBT activity without entering the circulation system. This non-systemic character of ASBT inhibitors implies a low risk of potential systemic toxicity and drug-drug interactions [12,13]. So far, a number of ASBT inhibitors having various structural characteristics have been synthesized.…”

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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“…To our knowledge, no study has investigated the ability of FDA-approved drugs to inhibit ASBT in vitro . Several ASBT inhibitors that were developed as potential cholesterol-lowering drugs are not been approved to date 33-43. In the present study, the most potent ASBT inhibitors were largely dihydropyridine, CCBs and statins.…”

Section: Discussionmentioning

confidence: 72%

“…Several ASBT inhibitors have been developed as novel cholesterol-lowering compounds, 33-35 including 2164U90, 36, 37 S-8921, 38, 39 SC-435, 40, 41 S-0960, 42 and R-146224 43. Structure-binding activity relationships for the ASBT have been previously described 44, 45.…”

Section: Introductionmentioning

confidence: 99%

Computational Models for Drug Inhibition of the Human Apical Sodium-Dependent Bile Acid Transporter

et al. 2009

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The human apical sodium-dependent bile acid transporter (ASBT; SLC10A2) is the primary mechanism for intestinal bile acid re-absorption. In the colon, secondary bile acids increase the risk of cancer. Therefore, drugs that inhibit ASBT have the potential to increase the risk of colon cancer. The objectives of this study were to identify FDA-approved drugs that inhibit ASBT and to derive computational models for ASBT inhibition. Inhibition was evaluated using ASBT-MDCK monolayers and taurocholate as the model substrate. Computational modeling employed a HipHop qualitative approach, a Hypogen quantitative approach, as well as a modified Laplacian Bayesian modeling method using 2D descriptors. Initially, 30 compounds were screened for ASBT inhibition. A qualitative pharmacophore was developed using the most potent 11 compounds and applied to search a drug database, yielding 58 hits. Additional compounds were tested and their K i values were measured. A 3D-QSAR and a Bayesian model were developed using 38 molecules. The quantitative pharmacophore consisted of one hydrogen bond acceptor, three hydrophobic features, and five excluded volumes. Each model was further validated with two external test sets of 30 and 19 molecules. Validation analysis showed both models exhibited good predictability in determining whether a drug is a potent or non-potent ASBT inhibitor. The Bayesian model correctly ranked the most active compounds. In summary, using a combined in vitro and computational approach, we found that many FDA-approved drugs from diverse classes, such as the dihydropyridine calcium channel blockers and HMG CoA-reductase inhibitors, are ASBT inhibitors.

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Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)

Cited by 44 publications

References 13 publications

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

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

Computational Models for Drug Inhibition of the Human Apical Sodium-Dependent Bile Acid Transporter

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