Design, synthesis, bioconversion, and pharmacokinetics evaluation of new ester prodrugs of olmesartan

Chang, Jeong-Soo; El‐Gamal, Mohammed I.; Lee, Woong San; Anbar, Hanan S.; Chung, Hanshik; Kim, Hyunil; Cho, Youngjin; Lee, Bong Sang; Lee, Sun Ahe; Moon, Ji Yun; Lee, Dong Jin; Jeon, Hong-Ryeol; Lee, Jaehwi; Choi, Young Wook; Oh, Chang‐Hyun

doi:10.1016/j.ejmech.2011.05.019

Cited by 6 publications

(5 citation statements)

References 10 publications

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“…Thus, we chose to synthesize only diester and bis-lactone prodrugs. The prodrug moieties that fit these criteria are pivaloxymethyl (e.g., drug, adefovir dipivoxyl, cefetamet pivoxil), , (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (e.g., lomesartan medoxomil, olmesartan medoxomil), , ethyl (e.g., xemilofiban), and lactone (e.g., lovastatin) . We incorporated concepts of these prodrug moieties and prepared a series of prodrugs.…”

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confidence: 99%

Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

Singh

Rindgen

Bradley

et al. 2013

ACS Med. Chem. Lett.

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Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.

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confidence: 99%

Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

Singh

Rindgen

Bradley

et al. 2013

ACS Med. Chem. Lett.

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“…Lesser emphasis was directed toward the synthesis of acyl derivatives of the C-8 secondary hydroxy group or carbamate derivatives of the pyrrolidine amino group of diesters to evaluate their potential role in absorption. Prodrug ester moieties that are part of successful clinical agents include pivaloxymethyl (e.g., adefovir dipivoxil, cefetamet pivoxil), , carbonate esters (e.g., tenoforvir disoproxil fumarate), (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (e.g., olmesartan medoxomil), , ethyl (e.g., xemilofiban), and lactones (e.g., lovastatin and simvastatin) . While preparing ertapenem prodrugs, we have incorporated the concepts of all of the promoieties and synthesized five ( 10 – 14 ) groups of prodrugs (Chart ).…”

Section: Resultsmentioning

confidence: 99%

“…15 While preparing ertapenem prodrugs, we have incorporated the concepts of all of the promoieties and synthesized five (10−14) groups of prodrugs (Chart 2). The prodrugs are bis-acyloxylmethyl esters (10), bis-(alkoxycarbonyl)oxy methyl esters (11), bis(alkoxy-2-oxo-1,3dioxol-4-yl) methyl esters (12), bis-alkyl esters (13), and macrocyclic-lactones (14). We recently reported a preliminary account of the synthesis and evaluation of a member (10a, 12a, 13a, and 14a) of each group except for the carbonate series 11.…”

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confidence: 99%

Design, Synthesis, Structure–Function Relationship, Bioconversion, and Pharmacokinetic Evaluation of Ertapenem Prodrugs

et al. 2014

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Described here are synthesis and biological evaluations of diversified groups of over 57 ertapenem prodrugs which include alkyl, methylenedioxy, carbonate, cyclic carbonate, carbamate esters, and esters containing active transport groups (e.g., carboxyl, amino acid, fatty acids, cholesterol) and macrocyclic lactones linking the two carboxyl groups. Many of the prodrugs were rapidly hydrolyzed in rat plasma but not in human plasma and were stable in simulated gastrointestinal fluid. The diethyl ester prodrug showed the best total absorption (>30%) by intredeudenal dosing in dogs, which could potentially be improved by formulation development. However, its slow rate of the hydrolysis to ertapenem also led to the presence of large amounts of circulating monoester metabolites, which pose significant development challenges. This study also suggests that the size of susbtituents at C-2 of carbapenem (e.g., benzoic acid of ertapenem) has significant impact on the absorption and the hydrolysis of the prodrugs.

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“…At the appropriate time, the corresponding whole blood sample was removed and treated with 0.5 mL of cold acetonitrile, then centrifuged at 4000 rpm for 5 min. The supernatant was diluted with deionized water and 20 µL of the supernatant was then injected into LC-MS/MS (Liu, 2007;Chang et al, 2011).…”

Section: Stabilities In Rat Whole Bloodmentioning

confidence: 99%

A Phenolic Ester of <i>O</i>-Desmethylvenlafaxine (ODV) Improves Uptake of ODV into the Brain

Zhang¹,

Yang²,

Zhao³

et al. 2016

American Journal of Biochemistry and Biotechnology

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In this study, the in vitro stabilities of a promising ODesmethylvenlafaxine (ODV) phenolic ester prodrug O-19 in aqueous solution, rat whole blood and rat liver microsomes were investigated. In addition, the in vivo drug metabolites were determined using LC-TOFMS-IDA-MS/MS. O-19 exhibits high stabilities at any pH encountered in the gastrointestinal tract, its half live (t 1/2 ) spans the range 5.0±0.18 d ~ 686±29.5 d. However, O-19 experiences rapid enzymatic hydrolysis in rat whole blood (t 1/2 = 3.6±0.53 min) and rat liver microsomes (t 1/2 = 9.5±1.53 min). The metabolic profile of O-19 is similar to that of ODV. Besides ODV itself, five metabolites are identified in rat urine (M 1~M5 ) and faeces (M 1 , M 4 ), no obvious toxic metabolite is detected.

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Design, synthesis, bioconversion, and pharmacokinetics evaluation of new ester prodrugs of olmesartan

Cited by 6 publications

References 10 publications

Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

Design, Synthesis, and Evaluation of Prodrugs of Ertapenem

Design, Synthesis, Structure–Function Relationship, Bioconversion, and Pharmacokinetic Evaluation of Ertapenem Prodrugs

A Phenolic Ester of <i>O</i>-Desmethylvenlafaxine (ODV) Improves Uptake of ODV into the Brain

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