Novel Potent and Efficacious Nonpeptidic Urotensin II Receptor Agonists

Lehmann, Fredrik; Pettersen, Anna; Currier, Erika A.; Sherbukhin, Vladimir; Olsson, Roger; Hacksell, Uli; Luthman, Kristina

doi:10.1021/jm051121i

Cited by 31 publications

(11 citation statements)

References 34 publications

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“…In addition to sEH inhibitors, the 1, 3-disubstituted urea moiety is frequently used in medicinal chemistry and is reported to possess various biological activities [71–78]. For example, many of the kinase inhibitors, including the marketed anticancer drugs sorafenib and regorafenib, have 1, 3-disubstituted urea-based structure with antitumor activity [79].…”

Section: Resultsmentioning

confidence: 99%

Occurrence of urea-based soluble epoxide hydrolase inhibitors from the plants in the order Brassicales

et al. 2017

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Recently, dibenzylurea-based potent soluble epoxide hydrolase (sEH) inhibitors were identified in Pentadiplandra brazzeana, a plant in the order Brassicales. In an effort to generalize the concept, we hypothesized that plants that produce benzyl glucosinolates and corresponding isothiocyanates also produce these dibenzylurea derivatives. Our overall aim here was to examine the occurrence of urea derivatives in Brassicales, hoping to find biologically active urea derivatives from plants. First, plants in the order Brassicales were analyzed for the presence of 1, 3-dibenzylurea (compound 1), showing that three additional plants in the order Brassicales produce the urea derivatives. Based on the hypothesis, three dibenzylurea derivatives with sEH inhibitory activity were isolated from maca (Lepidium meyenii) roots. Topical application of one of the identified compounds (compound 3, human sEH IC50 = 222 nM) effectively reduced pain in rat inflammatory pain model, and this compound was bioavailable after oral administration in mice. The biosynthetic pathway of these urea derivatives was investigated using papaya (Carica papaya) seed as a model system. Finally, a small collection of plants from the Brassicales order was grown, collected, extracted and screened for sEH inhibitory activity. Results show that several plants of the Brassicales order could be potential sources of urea-based sEH inhibitors.

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Section: Resultsmentioning

confidence: 99%

Occurrence of urea-based soluble epoxide hydrolase inhibitors from the plants in the order Brassicales

et al. 2017

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“…11, compound 18, Acadia Pharmaceuticals; EC 50 : 32 nM) and its optimized (+)-(S)-naphtyl-containing derivative (Fig. 11, compound 19, Acadia Pharmaceuticals; EC 50 : 23 nM) (Lehmann et al, 2006(Lehmann et al, , 2009.…”

Section: Design Of Nonpeptidic Urotensin II Receptor Agonists and mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

Vaudry

Leprince

Chatenet

et al. 2015

Pharmacological Reviews

143

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“…Alternatively, non‐acidic approaches to methylation exist that may obviate the above concerns. In this study, we tested a non‐acidic method using 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDCI) as a coupling reagent with 4‐dimethylaminopyridine (DMAP) as the catalyst (Figure ) . Carbodiimides, due to their accessibility and versatility, are ranked as one of the most important classes of compounds in organic chemistry .…”

Section: Introductionmentioning

confidence: 99%

Comparison of three methods for the methylation of aliphatic and aromatic compounds

Lee

Feakins

Lü

et al. 2017

Rapid Comm Mass Spectrometry

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RationaleMethylation protocols commonly call for acidic, hot conditions that are known to promote organic 1 H/ 2 H exchange in aromatic and aliphatic C-H bonds. Here we tested two such commonly-used methods and compared a third that avoids these acidic conditions, to quantify isotope effects with each method and to directly determine acidic-exchange rates relevant to experimental conditions. MethodsWe compared acidic and non-acidic methylation approaches catalyzed by hydrochloric acid, acetyl chloride and EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) / DMAP (4-dimethylaminopyridine) respectively. These were applied to two analytes: phthalic acid (an aromatic) and octacosanoic acid (an aliphatic). We analyzed yield by gas chromatography flame ionization (GC/FID) and hydrogen and carbon isotopic composition by isotope ratio mass spectrometry (GC/IRMS). We quantified the 1 H/ 2 H exchange rate on dimethyl phthalate under acidic conditions with proton nuclear magnetic resonance ( 1 H-NMR) measurements. ResultsThe δ 2 H and δ 13 C values and yield were equivalent among the three methods for methyl octacosanoate. The two acidic methods resulted in comparable yield and isotopic composition of dimethyl phthalate; however, the non-acidic method resulted in lower δ 2 H and δ 13 C values perhaps due to low yields. Concerns over acid-catalyzed 1 H/ 2 H exchange are unwarranted as the effect was trivial over a 12-hour reaction time.This article is protected by copyright. All rights reserved. ConclusionsWe find product isolation yield and evaporation to be the main concerns in the accurate determination of isotopic composition. 1 H/ 2 H exchange reactions are too slow to cause measurable isotope fractionation over the typical duration and reaction conditions used in methylation. Thus, we are able to recommend continued use of acidic catalysts in such methylation reactions for both aliphatic and aromatic compounds.

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Novel Potent and Efficacious Nonpeptidic Urotensin II Receptor Agonists

Cited by 31 publications

References 34 publications

Occurrence of urea-based soluble epoxide hydrolase inhibitors from the plants in the order Brassicales

Occurrence of urea-based soluble epoxide hydrolase inhibitors from the plants in the order Brassicales

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

Comparison of three methods for the methylation of aliphatic and aromatic compounds

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