Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists

Ivachtchenko, Alexandre V.; Golovina, Elena S.; Кадиева, M. Г.; Koryakova, Angela G.; Kovalenko, Sergiy M.; Mitkin, Oleg D.; Okun, Ilya; Ravnyeyko, Irina M.; Ткаченко, С. Е.; Zaremba, Oleg V.

doi:10.1016/j.bmc.2010.05.051

Cited by 27 publications

(13 citation statements)

References 16 publications

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“…Class D inhibitors are structural analogs of the triazolothienopyrimidine UTB inh -14 that we previously reported as a UT-B-selective inhibitor (Anderson et al, 2012). This general scaffold has antagonist activity against 5-HT 6 receptors in vitro (Ivachtchenko et al, 2010). Synthesis of each of the four inhibitor classes can be accomplished in a modular manner, allowing diversification of the scaffold to improve physicochemical properties for follow-up medicinal chemistry.…”

Section: Discussionmentioning

confidence: 99%

A Small Molecule Screen Identifies Selective Inhibitors of Urea Transporter UT-A

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Phuan

Anderson

2013

Chemistry & Biology

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SUMMARY Urea transporter (UT) proteins, including UT-A in kidney tubule epithelia and UT-B in vasa recta microvessels, facilitate urinary concentrating function. A screen for UT-A inhibitors was developed in MDCK cells expressing UT-A1, water channel aquaporin-1, and YFP-H148Q/V163S. An inwardly directed urea gradient produces cell shrinking followed by UT-A1-dependent swelling, which was monitored by YFP-H148Q/V163S fluorescence. Screening of ~90,000 synthetic small molecules yielded four classes of UT-A1 inhibitors with low micromolar IC50 that fully and reversibly inhibited urea transport by a non-competitive mechanism. Structure-activity analysis of >400 analogs revealed UT-A1-selective and UT-A1/UT-B non-selective inhibitors. Docking computations based on homology models of UT-A1 suggested inhibitor binding sites. UT-A inhibitors may be useful as diuretics (‘urearetics’) with a novel mechanism of action that may be effective in fluid-retaining conditions in which conventional salt transport-blocking diuretics have limited efficacy.

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Section: Discussionmentioning

confidence: 99%

A Small Molecule Screen Identifies Selective Inhibitors of Urea Transporter UT-A

Esteva‐Font

Phuan

Anderson

2013

Chemistry & Biology

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“…17 The arylsulfonylacetonitrile building blocks were first synthesized (Scheme 1). Commercially available substituted arylthiols ( 4a–4g ) were alkylated with bromoacetonitrile to generate the corresponding sulfides ( 5a–5g ), which were then oxidized with mCPBA to give the desired arylsulfonylacetonitriles 6a–6g .…”

Section: Resultsmentioning

confidence: 99%

Nanomolar Potency and Metabolically Stable Inhibitors of Kidney Urea Transporter UT-B

et al. 2012

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Urea transporters, which include UT-B in kidney microvessels, are potential targets for development of drugs with a novel diuretic (‘urearetic’) mechanism. We recently identified, by high-throughput screening, a triazolothienopyrimidine UT-B inhibitor, 1, that selectively and reversibly inhibited urea transport with IC50 = 25.1 nM and reduced urinary concentration in mice (Yao et al. J. Am. Soc. Nephrol., in press). Here, we analyzed 273 commercially available analogues of 1 to establish a structure–activity series and synthesized a targeted library of 11 analogues to identify potent, metabolically stable UT-B inhibitors. The best compound, {3-[4-(1,1-difluoroethyl)benzenesulfonyl]thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}thiophen-2-ylmethylamine, 3k, had IC50 of 23 and 15 nM for inhibition of urea transport by mouse and human UT-B, respectively, and ~40-fold improved in vitro metabolic stability compared to 1. In mice, 3k accumulated in kidney and urine and reduced maximum urinary concentration. Triazolothienopyrimidines may be useful for therapy of diuretic-refractory edema in heart and liver failure.

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“…IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1 H NMR spectra were recorded on a Bruker DRX-300 Avance spectrometer at 300.13 MHz and 13 C NMR spectra were recorded on a Bruker DRX-400 Avance spectrometer at 100.65 MHz using DMSO-d 6 and TMS as solvent and reference, respectively; chemical shifts (δ scale) are reported in parts per million (ppm). 1 H NMR spectra are reported in order: number of protons, multiplicity, and approximate coupling constant (J value) in hertz (Hz); signals were characterized as singlet (s), doublet (d), triplet (t), multiplet (m), broad signal (br s), and aryl (Ar).…”

Section: Experimental General Experimentalmentioning

confidence: 99%

“…Among their important effects, some triazolopyrimidine derivatives are known as blood pressure regulators [4], antibacterial agents [5], selective serotonin 5-HT6 receptor antagonists [6], and cardiovascular vasodilators [7]. In addition, several triazolopyrimidine-2-sulfonamide derivatives with herbicidal activity such as florasulam, flumetsulam, and metosulam are produced commercially [8].…”

Section: Introductionmentioning

confidence: 99%

One-pot four-component synthesis of highly substituted [1,2,4]triazolo[1,5-a]pyrimidines

et al. 2015

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Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists

Cited by 27 publications

References 16 publications

A Small Molecule Screen Identifies Selective Inhibitors of Urea Transporter UT-A

A Small Molecule Screen Identifies Selective Inhibitors of Urea Transporter UT-A

Nanomolar Potency and Metabolically Stable Inhibitors of Kidney Urea Transporter UT-B

One-pot four-component synthesis of highly substituted [1,2,4]triazolo[1,5-a]pyrimidines

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