Chemical synthesis of an indomethacin ester prodrug and its metabolic activation by human carboxylesterase 1

Takahashi, Masato; Ogawa, Tomohiro; Kashiwagi, Hiroshi; Fukushima, Fumiya; Yoshitsugu, Misaki; Haba, Masami; Hosokawa, Masakiyo

doi:10.1016/j.bmcl.2018.02.035

Cited by 20 publications

(10 citation statements)

References 23 publications

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“…The alkyl esters of RA remained stable during 5 h at room temperature in solution, while they converted to RA instantly in fresh plasma due to enzymatic hydrolysis (data not shown). As shown by others for ester-prodrugs of indomethacin and fusidic acid (Takahashi et al, 2018;Strydom et al, 2020), the alkyl esters of RA in our study were also hydrolyzed to form RA in vivo. Therefore, we developed and validated an UHPLC-MS/MS method to analyze the plasma concentration of RA after intravenous and oral administration of RA, RAME, RAET, RABU, RAOCT, RADOD in rats.…”

Section: In Vivo Bioavailability Of Rosmarinic Acid and Its Esterssupporting

confidence: 80%

Short Chain (≤C4) Esterification Increases Bioavailability of Rosmarinic Acid and Its Potency to Inhibit Vascular Smooth Muscle Cell Proliferation

et al. 2021

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Rosmarinic acid is a natural phenolic acid and active compound found in many culinary plants, such as rosemary, mint, basil and perilla. Aiming to improve the pharmacokinetic profile of rosmarinic acid and its activity on vascular smooth muscle cell proliferation, we generated a series of rosmarinic acid esters with increasing alkyl chain length ranging from C1 to C12. UHPLC-MS/MS analysis of rat blood samples revealed the highest increase in bioavailability of rosmarinic acid, up to 10.52%, after oral administration of its butyl ester, compared to only 1.57% after rosmarinic acid had been administered in its original form. When added to vascular smooth muscle cells in vitro, all rosmarinic acid esters were taken up, remained esterified and inhibited vascular smooth muscle cell proliferation with IC50 values declining as the length of alkyl chains increased up to C4, with an IC50 of 2.84 µM for rosmarinic acid butyl ester, as evident in a resazurin assay. Vascular smooth muscle cells were arrested in the G0/G1 phase of the cell cycle and the retinoblastoma protein phosphorylation was blocked. Esterification with longer alkyl chains did not improve absorption and resulted in cytotoxicity in in vitro settings. In this study, we proved that esterification with proper length of alkyl chains (C1–C4) is a promising way to improve in vivo bioavailability of rosmarinic acid in rats and in vitro biological activity in rat vascular smooth muscle cells.

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Section: In Vivo Bioavailability Of Rosmarinic Acid and Its Esterssupporting

confidence: 80%

Short Chain (≤C4) Esterification Increases Bioavailability of Rosmarinic Acid and Its Potency to Inhibit Vascular Smooth Muscle Cell Proliferation

et al. 2021

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“…Thus, an exquisite ester, which is labile to carboxylesterase 1 (CES1) in the liver, was added to compounds 4 and 5 to make prodrugs. [65] Metabolism of these prodrugs in hepatocytes revealed the active zwitterion that was retained by its poor passive permeability. Finally, compound 6 (PF-06815345) was selected as a candidate, as it was relatively well tolerated in 28 day preclinical toxicity studies in rats and monkeys.…”

Section: Approaches To Pcsk9 Inhibitionmentioning

confidence: 99%

Small molecules as inhibitors of PCSK9: Current status and future challenges

Luo

Zhu

et al. 2019

European Journal of Medicinal Chemistry

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed.

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“…The yellow precipitate was formed, filtered with cold water and recrystallized by methanol. 35,36 General procedure for the synthesis of pyrazoline derivatives, 3…”

Section: Generalmentioning

confidence: 99%

“…1 One of the primary strategies to develop novel drugs is the modification of well-known non-selective NSAIDs. 2,3 Some studies have shown that the derivatization of the carboxylate function of representative NSAIDs could increase anti-inflammatory activity while reducing gastrointestinal side effects. [4][5][6][7] The cyclooxygenase (COX) binding site is a hydrophobic channel.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, preliminary pharmacological evaluation, molecular docking and ADME studies of some new pyrazoline, isoxazoline and pyrimidine derivatives bearing nabumetone moiety targeting cyclooxygenase enzyme

Yousif

Mahdi

Raauf

2019

J. Contemp. Med. Sci.

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Nabumetone is a prodrug, its active metabolite 6-methoxy-2-naphthylacetic (6MNA) acid has low selectivity toward COX-2 enzyme; PLP fitness was 67.36 Kcal/Mol. A series of pyrazolines, oxazolines and pyrimidines bearing nabumetone moiety have been designed, synthesized, and evaluated as a potential cyclooxygenase-2 (COX-2) inhibitors. These new compounds were evaluated for their in vivo anti-inflammatory activity and in vitro COX-2 selectivity through molecular docking via GOLD suite v. 5.6.2. All tested compounds in molecular docking exhibited significant activities compared with diclofenac, naproxen, and 6MNA as reference drugs due to their hydrogen bonding interaction with key amino acids in COX isozymes Arg120, Tyr355, and Ser530, and these results are compatible with their in vivo acute anti-inflammatory study for tested compounds. Also, ADME studies were performed to predict which of them are candidate to be given orally, site of absorption, bioavailability, topological polar surface area and drug-likeness. The ADME results showed that all synthesized compounds absorbed from GIT while, only compounds 3, 2a, 2c, and 3a -3c fulfilled the Lipinski rule.

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Chemical synthesis of an indomethacin ester prodrug and its metabolic activation by human carboxylesterase 1

Cited by 20 publications

References 23 publications

Short Chain (≤C4) Esterification Increases Bioavailability of Rosmarinic Acid and Its Potency to Inhibit Vascular Smooth Muscle Cell Proliferation

Short Chain (≤C4) Esterification Increases Bioavailability of Rosmarinic Acid and Its Potency to Inhibit Vascular Smooth Muscle Cell Proliferation

Small molecules as inhibitors of PCSK9: Current status and future challenges

Design, synthesis, preliminary pharmacological evaluation, molecular docking and ADME studies of some new pyrazoline, isoxazoline and pyrimidine derivatives bearing nabumetone moiety targeting cyclooxygenase enzyme

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