Structure−Activity Relationship Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a Potent Inhibitor of Leukotriene A<sub>4</sub> (LTA<sub>4</sub>) Hydrolase

Penning, Thomas D.; Chandrakumar, Nizal S.; Chen, B B; Chen, H Y; Desai, B. N.; Djurić, Stevan W.; Docter, Stephen H.; Gasiecki, Alan F.; Haack, Richard A.; Miyashiro, Julie M.; Russell, Mark A.; Yu, Stella S.; Corley, David G.; Durley, Richard C.; Kilpatrick, Brian F.; Parnas, Barry L.; Askonas, Leslie J.; Gierse, James K.; Harding, Elizabeth I.; Highkin, Maureen; Kachur, James F.; Kim, S H; Krivi, Gwen G.; Villani-Price, Doreen; Pyla, E.Yvonne; Smith, Walter G.

doi:10.1021/jm990496z

Cited by 64 publications

(47 citation statements)

References 29 publications

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“…The phenol function was substituted with polar and potentially charged groups such as N,N -dimethylaminoethylene group (compounds 11–13 ), morpholinoethylene group (compounds 15–17 ) and piperazinoethylene group (compounds 23–25 ), which are widely used in medicinal chemistry to enhance aqueous solubility. 40 Alternatively, we have attempted to extend the putative pharmacophore by the use of 2-amino-3-hydroxypyridine (compounds 26–28 ) as one of the N -aryl moieties comprising the non-symmetrical N,N’ -diarylureas. Similar introduction of a 3-hydroxypyridin-2-yl ring into N,N’ -diarylureas was previously reported for inhibitors of insulin-like growth factor I receptor and resulted in ureas with good biological activity.…”

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confidence: 99%

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

Denoyelle

Chen

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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Symmetrical N,N’-diarylureas: 1,3-bis(3,4-dichlorophenyl)-, 1,3-bis[4-chloro-3(trifluoromethyl) phenyl]- and 1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea, were identified as potent activators of the eIF2α kinase heme regulated inhibitor. They reduce the abundance of the eIF2·GTP·tRNAiMet ternary complex and inhibit cancer cell proliferation. An optimization process was undertaken to improve their solubility while preserving their biological activity. Non-symmetrical hybrid ureas were generated by combining one of the hydrophobic phenyl moieties present in the symmetrical ureas with the polar 3-hydroxy-tolyl moiety. O-alkylation of the later added potentially solubilizing charge bearing groups. The new non-symmetrical N,N’-diarylureas were characterized by ternary complex reporter gene and cell proliferation assays, demonstrating good bioactivities. A representative sample of these compounds potently induced phosphorylation of eIF2α and expression of CHOP at the protein and mRNA levels. These inhibitors of translation initiation may become leads for the development of potent, non-toxic, and target specific anti-cancer agents.

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confidence: 99%

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

Denoyelle

Chen

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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“…This resulted in the corresponding coupled product containing a carbinol in the methylene bridge connecting the two fragments. The carbinol and t-butyl ester were then removed by treating with TFA and triethylsilane 23 resulting in the key intermediate 6 in gram quantities and a 55% overall yield for the two steps.…”

Section: Resultsmentioning

confidence: 99%

Sobetirome prodrug esters with enhanced blood–brain barrier permeability

Placzek

Ferrara

Hartley

et al. 2016

Bioorganic & Medicinal Chemistry

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There is currently great interest in developing drugs that stimulate myelin repair for use in demyelinating diseases such as multiple sclerosis. Thyroid hormone plays a key role in stimulating myelination during development and also controls the expression of important genes involved in myelin repair in adults. Because endogenous thyroid hormone in excess lacks a generally useful therapeutic index, it is not used clinically for indications other than hormone replacement; however, selective thyromimetics such as sobetirome offer a therapeutic alternative. Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood-brain-barrier (BBB) and we endeavored to increase the BBB permeability of sobetirome using a prodrug strategy. Ester prodrugs of sobetirome were prepared based on literature reports of improved BBB permeability with other carboxylic acid containing drugs and BBB permeability was assessed in vivo. One sobetirome prodrug, ethanolamine ester 11, was found to distribute more sobetirome to the brain compared to an equimolar peripheral dose of unmodified sobetirome. In addition to enhanced brain levels, prodrug 11 displayed lower sobetirome blood levels and a brain/serum ratio that was larger than that of unmodified sobetirome. Thus, these data indicate that an ester prodrug strategy applied to sobetirome can deliver increased concentrations of the active drug to the central nervous system (CNS), which may prove useful in the treatment of CNS disorders.

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“…26 We started with 1-(2-(4-phenoxyphenoxy)ethyl)-pyrrolidine, an LTA4H inhibitor reported by Penning et al, 40 and nimesulide, a COX-2 selective NSAID used clinically, which are compounds that share the same phenoxyphenyl scaffold. Subsequently, a series of 1-(2-(4-phenoxyphenoxy)-ethyl)pyrrolidine derivatives were synthesized and tested.…”

Section: Ligand Mergingmentioning

confidence: 99%

Diverse Ways of Perturbing the Human Arachidonic Acid Metabolic Network To Control Inflammation

2015

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Inflammation and other common disorders including diabetes, cardiovascular disease, and cancer are often the result of several molecular abnormalities and are not likely to be resolved by a traditional single-target drug discovery approach. Though inflammation is a normal bodily reaction, uncontrolled and misdirected inflammation can cause inflammatory diseases such as rheumatoid arthritis and asthma. Nonsteroidal anti-inflammatory drugs including aspirin, ibuprofen, naproxen, or celecoxib are commonly used to relieve aches and pains, but often these drugs have undesirable and sometimes even fatal side effects. To facilitate safer and more effective anti-inflammatory drug discovery, a balanced treatment strategy should be developed at the biological network level. In this Account, we focus on our recent progress in modeling the inflammation-related arachidonic acid (AA) metabolic network and subsequent multiple drug design. We first constructed a mathematical model of inflammation based on experimental data and then applied the model to simulate the effects of commonly used anti-inflammatory drugs. Our results indicated that the model correctly reproduced the established bleeding and cardiovascular side effects. Multitarget optimal intervention (MTOI), a Monte Carlo simulated annealing based computational scheme, was then developed to identify key targets and optimal solutions for controlling inflammation. A number of optimal multitarget strategies were discovered that were both effective and safe and had minimal associated side effects. Experimental studies were performed to evaluate these multitarget control solutions further using different combinations of inhibitors to perturb the network. Consequently, simultaneous control of cyclooxygenase-1 and -2 and leukotriene A4 hydrolase, as well as 5-lipoxygenase and prostaglandin E2 synthase were found to be among the best solutions. A single compound that can bind multiple targets presents advantages including low risk of drug-drug interactions and robustness regarding concentration fluctuations. Thus, we developed strategies for multiple-target drug design and successfully discovered several series of multiple-target inhibitors. Optimal solutions for a disease network often involve mild but simultaneous interventions of multiple targets, which is in accord with the philosophy of traditional Chinese medicine (TCM). To this end, our AA network model can aptly explain TCM anti-inflammatory herbs and formulas at the molecular level. We also aimed to identify activators for several enzymes that appeared to have increased activity based on MTOI outcomes. Strategies were then developed to predict potential allosteric sites and to discover enzyme activators based on our hypothesis that combined treatment with the projected activators and inhibitors could balance different AA network pathways, control inflammation, and reduce associated adverse effects. Our work demonstrates that the integration of network modeling and drug discovery can provide novel solutions for disease...

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Structure−Activity Relationship Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a Potent Inhibitor of Leukotriene A₄ (LTA₄) Hydrolase

Cited by 64 publications

References 29 publications

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

Sobetirome prodrug esters with enhanced blood–brain barrier permeability

Diverse Ways of Perturbing the Human Arachidonic Acid Metabolic Network To Control Inflammation

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Structure−Activity Relationship Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a Potent Inhibitor of Leukotriene A4 (LTA4) Hydrolase

Cited by 64 publications

References 29 publications

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

In vitro inhibition of translation initiation by N,N′-diarylureas—potential anti-cancer agents

Sobetirome prodrug esters with enhanced blood–brain barrier permeability

Diverse Ways of Perturbing the Human Arachidonic Acid Metabolic Network To Control Inflammation

Contact Info

Product

Resources

About

Structure−Activity Relationship Studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a Potent Inhibitor of Leukotriene A₄ (LTA₄) Hydrolase