Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 1: Design, synthesis and structure–activity relationship studies

Vergne, Fabrice; Bernardelli, Patrick; Lorthiois, Edwige; Pham, Nga; Proust, Emmanuelle; Oliveira, Chrystelle; Mafroud, Abdel-Kader; Royer, Frederique; Wrigglesworth, Roger; Schellhaas, Jennifer K.; Barvian, Mark R.; Moreau, F.; Idrissi, Moulay; Tertre, Anita; Bertin, Bernadette; Coupe, Magali; Berna, Patrick; Soulard, Patricia

doi:10.1016/j.bmcl.2004.07.008

Cited by 57 publications

(24 citation statements)

References 21 publications

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“…This compound has an IC 50 against PDE7A of 370 nM (at 32 nM cAMP) and has a similar isoenzyme selectivity profile to BRL 50481 (Lee et al, 2002). Several series of compounds from Pfizer and Bristol-Myers Squibb with PDE7 inhibitory activity have also Pitts et al, 2004;Vergne et al, 2004). One of these, BMS-586353, is a potent (IC 50 value of 8 nM), bioavailable inhibitor of PDE7 with excellent selectivity relative to other PDE isoenzyme families (3722-, 6277-, 1250-, 1231-, and 553-fold less potent against PDE1, PDE3, PDE4, PDE5, and PDE6, respectively; Yang et al, 2003).…”

Section: Discussionmentioning

confidence: 96%

Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8⁺T-Lymphocytes

Smith¹,

Cieslinski²,

Newton³

et al. 2004

Mol Pharmacol

154

123

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The biochemical and pharmacological characteristics in human proinflammatory cells of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a novel and selective inhibitor of phosphodiesterase (PDE) 7, are described. BRL 50481 inhibited the activity of hrPDE7A1 expressed in baculovirus-infected Spodoptera frugiperda 9 cells in a competitive manner (K i value of 180 nM) and was 416 and 1884 times less potent against PDE3 and 38 and 238 times less potent against PDE4 at a substrate concentration of 1 M and 50 nM cAMP, respectively. Western blotting identified HSPDE7A1 but not HSPDE7A2 in three human cell types that are implicated in the pathogenesis of chronic obstructive lung disease, namely, CD8 ϩ T-lymphocytes, monocytes, and lung macrophages. BRL 50481 had no effect on the proliferation of CD8 ϩ Tlymphocytes and only marginally (ϳ2-11%) reduced the generation of tumor necrosis factor (TNF)␣ from blood monocytes and lung macrophages. However, in the presence of BRL 50481 the inhibitory effect of rolipram was enhanced on all three cell types. The expression of HSPDE7A1 was increased in a time-dependent manner in monocytes that were "aged" in culture medium. Under this condition, BRL 50481 now inhibited TNF␣ generation in a concentration-dependent manner. In aged monocytes, rolipram, Org 9935 (a PDE3 inhibitor), and prostaglandin E 2 inhibited TNF␣ generation in a concentrationdependent manner and interacted additively with BRL 50481. BRL 50481 is the first fully documented PDE7 inhibitor that has acceptable selectivity for in vitro studies. Furthermore, although BRL 50481 had only a modest inhibitory effect per se on the proinflammatory cells studied, it acted at least additively with other cAMP-elevating drugs, especially when HSPDE7A1 was up-regulated.

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Section: Discussionmentioning

confidence: 96%

Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8⁺T-Lymphocytes

Smith¹,

Cieslinski²,

Newton³

et al. 2004

Mol Pharmacol

154

123

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“…The data set is characterized by a high structural diversity since it is formed by iminothiadiazoles, 28,29 benzene sulfonamides, 30 quinazolines, 16 thiazoles, 31 and spirotricyclic derivatives, 32 among others (Figure 1). …”

mentioning

confidence: 99%

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

Redondo

Palomo

Brea

et al. 2012

ACS Chem. Neurosci.

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A neural network model has been developed to predict the inhibitory capacity of any chemical structure to be a phosphodiesterase 7 (PDE7) inhibitor, a new promising kind of drugs for the treatment of neurological disorders. The numerical definition of the structures was achieved using CODES program. Through the validation of this neural network model, a novel family of 5-imino-1,2,4-thiadiazoles (ITDZs) has been identified as inhibitors of PDE7.Experimental extensive biological studies have demonstrated the ability of ITDZs to inhibit PDE7 and to increase intracellular levels of cAMP. Among them, the derivative 15 showed a high in vitro potency with desirable pharmacokinetic profile (safe genotoxicity and blood brain barrier penetration). Administration of ITDZ 15 in an experimental autoimmune encephalomyelitis (EAE) mouse model results in a significant attenuation of clinical symptoms, showing the potential of ITDZs, especially compound 15, for the effective treatment of multiple sclerosis.

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“…Derivatives of 1,3,4-thiadiazole derivatives have in recent years been increasingly investigated by these means due to their diverse biological properties which include antimicrobial, anti-inflammatory, anticonvulsant, antidepressant, antioxidant, and most importantly of all anticancer activities [1]. These different actions result from how the 1,3,4-thiadiazole ring is modified in the various derivatives thus arising [2][3][4]. Indeed, previous studies by our group have described the synthesis of compounds belonging to the 2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole set [5][6][7] that exhibit in vitro anticancer and neuro-protective activity thereby suggesting a possible role in the future drug treatment of cancer and nervous system disease.…”

Section: Introductionmentioning

confidence: 99%

A simple HPLC method for determining 2-(3-chlorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole in brain and plasma of animals: Application to a pharmacokinetic study

Raszewski

Juszczak²,

Lemieszek³

et al. 2014

Acta Chromatographica

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Summary. The development, optimization, and validation of a new high-performance liquid chromatography ultraviolet (HPLC-UV) method is presented for determining 2-(3-chlorophenyloamino)-5-(2,4-dihydroxy-phenyl)-1,3,4-thiadiazole (ClABT) in biological samples of rat plasma and brain tissue. ClABT was extracted directly from a plasma supernatant fraction following protein precipitation with acetonitrile and high speed centrifugation. Reverse phase HPLC separation was performed using an ODS-2 Hypersil column with the mobile phase consisting of 0.05 M triethylammonium phosphate buffer solution in acetonitrile and methanol (120:280:600, v/v/v), at room temperature, 1.2 mL min −1 flow rate, and UV-diode-array detection (DAD), at 335 nm. A linear response was obtained between 12.5 and 2000 ng mL −1 at analytically acceptable levels of precision (intra/inter-day) and accuracy. Mean recoveries ranged from 92.7% to 107.9%. It was concluded that the method was specific and precise and thus suitable for quantitative analysis in clinical pharmacokinetic studies of ClABT.

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Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 1: Design, synthesis and structure–activity relationship studies

Cited by 57 publications

References 21 publications

Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8⁺T-Lymphocytes

Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8⁺T-Lymphocytes

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

A simple HPLC method for determining 2-(3-chlorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole in brain and plasma of animals: Application to a pharmacokinetic study

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Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 1: Design, synthesis and structure–activity relationship studies

Cited by 57 publications

References 21 publications

Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8+T-Lymphocytes

Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8+T-Lymphocytes

Identification in Silico and Experimental Validation of Novel Phosphodiesterase 7 Inhibitors with Efficacy in Experimental Autoimmune Encephalomyelitis Mice

A simple HPLC method for determining 2-(3-chlorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole in brain and plasma of animals: Application to a pharmacokinetic study

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Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8⁺T-Lymphocytes

Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8⁺T-Lymphocytes