Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors

Kehler, Jan; Ritzén, Andreas; Langgård, Morten; Petersen, Sebastian Leth; Farah, Mohamed M.; Bundgaard, Christoffer; Christoffersen, Claus T.; Nielsen, Jacob; Kilburn, John Paul

doi:10.1016/j.bmcl.2011.04.067

Cited by 47 publications

(32 citation statements)

References 19 publications

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“…The latter method was less effective than the previous because of a lower yield. It is important, that in all cases, intermediate [1,2,4]triazolo[4,3- c ]-quinazolines are ANRORC-rearranged forming 2-R-[1,2,4]triazolo[1,5- c ]quinazolines ( 5.1–5.40 ) [21]. The 1 H-NMR spectra of compounds 5.1–5.40 were significantly different from the spectra of hydrazides 3.1–3.40 and hydrazones 4.1–4.6 .…”

Section: Resultsmentioning

confidence: 99%

“…It is known, that [1,2,4]triazolo[1,5- c ]quinazoline derivatives possess adenosine and benzodiazepine receptor affinity [1, 2], antiasthmatic, tranquilizing, neurostimulating [3], phosphodiesterase 10A inhibitive [4], antimicrobial and antifungal [5–7], anti-inflammatory, and sedative activities [8, 9]. As a result, their derivatives surely will have biological activity because of the potent pharmacophore they have in their structures.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines

Коваленко

Antypenko²,

Bilyi³

et al. 2013

Sci. Pharm.

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The combinatorial library of novel potential anticancer agents, namely, 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines, was synthesized by the heterocyclization of the alkyl-, alkaryl-, aryl-, hetarylcarboxylic acid (3H-quinazoline-4-ylidene)hydrazides by oxidative heterocyclization of the 4-(arylidenehydrazino)quinazolines using bromine, and by the heterocyclization of N-(2-cyanophenyl)formimidic acid ethyl ester. The optimal method for synthesis of the s-triazolo[1,5-c]quinazolines appeared to be cyclocondensation of the corresponding carboxylic acid (3H-quinazoline-4-ylidene)hydrazides. The compounds’ structures were established by 1H, 13C NMR, LC- and EI-MS analysis. The in vitro screening of anticancer activity determined the most active compound to be 3,4,5-trimethoxy-N′-[quinazolin-4(3H)-ylidene]benzohydrazide (3.20) in micromolar concentrations with the GI50 level (MG_MID, GI50 is 2.29). Thus, the cancer cell lines whose growth is greatly inhibited by compound 3.20 are: non-small cell lung cancer (NCI-H522, GI50=0.34), CNS (SF-295, GI50=0.95), ovarian (OVCAR-3, GI50=0.33), prostate (PC-3, GI50=0.56), and breast cancer (MCF7, GI50=0.52), leukemia (K-562, GI50=0.41; SR, GI50=0.29), and melanoma (MDA-MB-435, GI50=0.31; SK-MEL-5, GI50=0.74; UACC-62, GI50=0.32). SAR-analysis is also discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines

Коваленко

Antypenko²,

Bilyi³

et al. 2013

Sci. Pharm.

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“…Therefore, because of the presence of PDE10A in the acrosomal region, it is tempting to hypothesize that it is somehow involved in the control of sperm acrosomal exocytosis. In fact, this appears to be the case as an increase in spontaneous acrosome reaction was observed when sperm are incubated with the specific PDE10 inhibitor MP10 [57] (data not shown, manuscript in preparation), while no effect on sperm motility was observed (63.0% ± 7.5 vs 66.3% ± 4.8 for control vs MP10-treated sperm). We previously showed that sperm cAMP concentration is correlated with the membrane-binding pattern of chlortetracycline (CTC, pattern B) that is generally observed in capacitated sperm [58, 59].…”

Section: Discussionmentioning

confidence: 99%

Identification and Localization of the Cyclic Nucleotide Phosphodiesterase 10A in Bovine Testis and Mature Spermatozoa

et al. 2016

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In mammals, adenosine 3’, 5’-cyclic monophosphate (cAMP) is known to play highly important roles in sperm motility and acrosomal exocytosis. It is known to act through protein phosphorylation via PRKA and through the activation of guanine nucleotide exchange factors like EPAC. Sperm intracellular cAMP levels depend on the activity of adenylyl cyclases, mostly SACY, though transmembrane-containing adenylyl cyclases are also present, and on the activity of cyclic nucleotide phosphodiesterases (PDE) whose role is to degrade cAMP into 5’-AMP. The PDE superfamily is subdivided into 11 families (PDE1 to 11), which act on either cAMP or cGMP, or on both cAMP and cGMP although with different enzymatic properties. PDE10, which is more effective on cAMP than cGMP, has been known for almost 15 years and is mostly studied in the brain where it is associated with neurological disorders. Although a high level of PDE10A gene expression is observed in the testis, information on the identity of the isoforms or on the cell type that express the PDE10 protein is lacking. The objective of this study was to identify the PDE10A isoforms expressed in the testis and germ cells, and to determine the presence and localization of PDE10A in mature spermatozoa. As a sub-objective, since PDE10A transcript variants were reported strictly through analyses of bovine genomic sequence, we also wanted to determine the nucleotide and amino acid sequences by experimental evidence. Using RT-PCR, 5’- and 3’-RACE approaches we clearly show that PDE10A transcript variants X3 and X5 are expressed in bovine testis as well as in primary spermatocytes and spermatids. We also reveal using a combination of immunological techniques and proteomics analytical tools that the PDE10A isoform X4 is present in the area of the developing acrosome of spermatids and of the acrosome of mature spermatozoa.

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“…In a later application, preparation of pyrazoloquinazoline derivatives and analogs like 7, 5-(1H-benzoimidazol-2-ylmethylsulfanyl)-2-methyl- [1,2,4]triazolo [1,5-c]quinazoline was claimed for use as PDE10A enzyme inhibitors [14], wherein the bicyclic triazolopyrimidine clamp motif of compound 1 was replaced by a tricyclic heterocycle. SAR studies and an X-ray structure for this series was recently published [15,16]. Also the Q2-pheyl imidazole motif could …”

Section: Recent Developments In the Field Of Patented Pde10a Inhibitomentioning

confidence: 98%

Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update

Kehler

2012

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Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors

Cited by 47 publications

References 19 publications

Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines

Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines

Identification and Localization of the Cyclic Nucleotide Phosphodiesterase 10A in Bovine Testis and Mature Spermatozoa

Phosphodiesterase 10A inhibitors: a 2009 – 2012 patent update

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