Tag: M.W=500-550

Micewicz, Ewa D. published the artcileIdentification of novel small-molecule inhibitors of Zika virus infection, Formula: C25H29N9O3, the publication is Bioorganic & Medicinal Chemistry Letters (2018), 28(3), 452-458, database is CAplus and MEDLINE.

The recent re-emergence of Zika virus (ZIKV), a member of the Flaviviridae family, has become a global emergency and a serious public health threat worldwide. ZIKV infection causes severe neuroimmunopathol. and is particularly harmful to the developing fetuses of infected pregnant women causing various developmental abnormalities. Currently, there are no effective methods of preventing or treating ZIKV infection, and new treatment options are urgently needed. Therefore, we have used an in vitro plaque assay to screen a limited proprietary library of small organic compounds and identified highly bioactive leads, with the most active analogs showing activity in low picomolar range. Identified “hits” possess certain common structural features that can be used in the design of the next generation(s) of ZIKV inhibitors. Collectively, our findings suggest that identified compounds represent excellent template(s) for the development of inexpensive and orally available anti-Zika drugs.

Bioorganic & Medicinal Chemistry Letters published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Formula: C25H29N9O3.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Zhou, Xiaoyun published the artcileSynthesis and Preclinical Evaluation of 2-(2-Furanyl)-7-[2-[4-[4-(2-[¹¹C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine ([¹¹C]Preladenant) as a PET Tracer for the Imaging of Cerebral Adenosine A_2A Receptors, Computed Properties of 377727-87-2, the publication is Journal of Medicinal Chemistry (2014), 57(21), 9204-9210, database is CAplus and MEDLINE.

2-(2-Furanyl)-7-[2-[4-[4-(2-[¹¹C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine [¹¹C]-3 ([¹¹C]Preladenant) was developed for mapping cerebral adenosine A_2A receptors (A_2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD), and in vitro autoradiog. (ARG) experiments Regional brain uptake of [¹¹C]-3 was consistent with known A_2ARs distribution, with highest uptake in striatum. The results indicate that [¹¹C]-3 has favorable brain kinetics and exhibits suitable characteristics as an A_2AR PET tracer.

Journal of Medicinal Chemistry published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C6H8O6, Computed Properties of 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Fong, Robert published the artcileCaffeine accelerates recovery from general anesthesia via multiple pathways, Quality Control of 377727-87-2, the publication is Journal of Neurophysiology (2017), 118(3), 1591-1597, database is CAplus and MEDLINE.

Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP. In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A2a adenosine receptor antagonist preladenant or the intracellular cAMP ([cAMP]i)-elevating drug forskolin, accelerated recovery from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP]i and adenosine receptor blockade play a role in this response.

Journal of Neurophysiology published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Quality Control of 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Hattori, Nobutaka published the artcileAdjunctive preladenant: A placebo-controlled, dose-finding study in Japanese patients with Parkinson’s disease., Application In Synthesis of 377727-87-2, the publication is Parkinsonism & related disorders (2016), 73-79, database is MEDLINE.

BACKGROUND: Preladenant, an adenosine 2A antagonist, reduced daily OFF time when administered as adjunctive treatment in a previous phase 2 trial in non-Japanese Parkinson’s disease (PD) patients on stable doses of levodopa. This study aimed to evaluate preladenant as adjunctive therapy in Japanese patients with PD. METHODS: In this randomized, placebo-controlled, double-blind, 12-week, dose-ranging, phase 2 study, Japanese patients with moderate to severe PD on a stable regimen of levodopa were randomly assigned 1:1:1:1 to preladenant 2 mg, 5 mg, or 10 mg BID or placebo. The primary efficacy end point was change from baseline to week 12 in mean OFF time, recorded using a PD diary. Safety and tolerability were also assessed. RESULTS: In total, 111 patients were randomly assigned to receive preladenant 2 mg, and 113 each received preladenant 5 mg, 10 mg, or placebo. In contrast to previous data, preladenant in this study did not demonstrate statistically significant efficacy; the primary outcome was -0.7 h (P = 0.0564), -0.5 h (P = 0.1844), and -0.3 h (P = 0.3386), respectively, for preladenant 2 mg, 5 mg, and 10 mg BID versus placebo. Overall, preladenant was well tolerated, and the frequency of adverse events appeared to be dose related. CONCLUSIONS: In this phase 2 study, preladenant used as adjunctive therapy in PD patients on stable doses of levodopa did not reduce mean OFF time; treatment was well tolerated at doses between 2 and 10 mg BID.

Parkinsonism & related disorders published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Application In Synthesis of 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Zhong, Wendy published the artcileInfluence of differently ionized species on fragmentation pathways and energetics of a potential adenosine receptor antagonist using a triple quadrupole and a multistage LTQ-Orbitrap FTMS instrument, Computed Properties of 377727-87-2, the publication is Journal of Heterocyclic Chemistry (2009), 46(4), 591-598, database is CAplus.

A systematic study was conducted to study the influence of differently ionized species on the fragmentation pathways and energetics of a piperazine-containing adenosine by using different cations or anions. Very different fragmentation mechanisms were observed in protonated- vs. sodiated-mols., which indicated that the proton is mobilized to promote the charge-direct fragmentation, whereas Na⁺ cation was fixed at the heterotricyclic ring structure provoking charge-remote fragment ions. This finding was also supported by the results observed in the fragmentation behaviors in the deprotonated-mol. The energetics of these fragment ions were also explored by using the breakdown curves obtained from the triple quadrupole and LTQ-Orbitrap instrument. The lowest energy pathways in the protonated-mol. [M+H]⁺ involve breaking a C-N bond connecting an ethylene bridge and heterotricyclic ring structure. The lowest energy pathway is the cleavage of a C-O bond connecting the methoxy Et group and phenolic oxygen to form a distonic radical ion for a sodiated-mol. [M+Na⁺]and a deprotonated-mol. [M-H]^–. Probably by choosing the differently ionized species, one can probe different fragmentation channels that can provide addnl. structure information for an unknown impurity and possibly degradation product identification. By comparing the data obtained from triple quadrupole and LTQ-Orbitrap instruments, one can develop further understanding of the differences in the fragmentation behaviors due to the variations in the collision activation-dissociation process. From the side-by-side comparison with the breakdown curves obtained for both instruments, the difference in fragmentation behaviors caused by the difference in dissociation processes that occur in these two types of instruments can be probed. J. Heterocyclic Chem., (2009).

Journal of Heterocyclic Chemistry published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C21H18N4OS, Computed Properties of 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Zhong, Wendy published the artcileIdentification of a Unique Cationic Impurity in Preladenant® Using Accurate MS and NMR, Safety of 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, the publication is Journal of Heterocyclic Chemistry (2013), 50(2), 281-287, database is CAplus.

High resolution MS, 1D, and 2D NMR were used to determine the structure of a unique cationic impurity generated during the synthesis of Preladenant® H/D exchange experiments were performed by both MS and NMR to confirm the acidic nature of the cationic dihydroimidazole proton. The presence of three exchangeable protons was established by MS experiments and the disappearance of the C11 proton in ¹H-NMR spectrum on equilibration with D₂O confirmed the acidic nature of the cationic dihydroimidazole proton. A piperazine ring contraction mechanism is proposed for the formation of the cationic dihydroimidazole.

Journal of Heterocyclic Chemistry published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C12H17NS2, Safety of 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Neustadt, Bernard R. published the artcilePotent, selective, and orally active adenosine A_2A receptor antagonists: Arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines, Formula: C25H29N9O3, the publication is Bioorganic & Medicinal Chemistry Letters (2007), 17(5), 1376-1380, database is CAplus and MEDLINE.

Antagonism of the adenosine A_2A receptor offers great promise in the treatment of Parkinson’s disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A_2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h (I), orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.

Bioorganic & Medicinal Chemistry Letters published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Formula: C25H29N9O3.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Barret, Olivier published the artcileAdenosine 2A receptor occupancy by tozadenant and preladenant in rhesus monkeys, Computed Properties of 377727-87-2, the publication is Journal of Nuclear Medicine (2014), 55(10), 1712-1718, database is CAplus and MEDLINE.

Motor symptoms in Parkinson disease (PD) are caused by a loss of dopamine input from the substantia nigra to the striatum. Blockade of adenosine 2A (A_2A) receptors facilitates dopamine D₂ receptor function. In phase 2 clin. trials, A_2A antagonists (istradefylline, preladenant, and tozadenant) improved motor function in PD. We developed a new A_2A PET radiotracer, ¹⁸F-MNI-444, and used it to investigate the relationship between plasma levels and A_2A occupancy by preladenant and tozadenant in nonhuman primates (NHP). Methods: A series of 20 PET experiments was conducted in 5 adult rhesus macaques. PET data were analyzed with both plasma-input (Logan graphical anal.) and reference-region-based (simplified reference tissue model and noninvasive Logan graphical anal.) methods. Whole-body PET images were acquired for radiation dosimetry estimates Human pharmacokinetic parameters for tozadenant and preladenant were used to predict A_2A occupancy in humans, based on median effective concentration (EC₅₀) values estimated from the NHP PET measurements. Results: ¹⁸F-MNI-444 regional uptake was consistent with A_2A receptor distribution in the brain. Selectivity was demonstrated by dose-dependent blocking by tozadenant and preladenant. The specific-to-nonspecific ratio was superior to that of other A_2A PET radiotracers. Pharmacokinetic modeling predicted that tozadenant and preladenant may have different profiles of A_2A receptor occupancy in humans. Conclusion: ¹⁸F-MNI-444 appears to be a better PET radiotracer for A_2A imaging than currently available radiotracers. Assuming that EC₅₀ in humans is similar to that in NHP, it appears that tozadenant will provide a more sustained A_2A receptor occupancy than preladenant in humans at clin. tested doses.

Journal of Nuclear Medicine published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C25H29N9O3, Computed Properties of 377727-87-2.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Sirci, Francesco published the artcileLigand-, structure- and pharmacophore-based molecular fingerprints: a case study on adenosine A₁, A_2A, A_2B, and A₃ receptor antagonists, Safety of 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, the publication is Journal of Computer-Aided Molecular Design (2012), 26(11), 1247-1266, database is CAplus and MEDLINE.

FLAP fingerprints are applied in the ligand-, structure- and pharmacophore-based mode in a case study on antagonists of all four adenosine receptor (AR) subtypes. Structurally diverse antagonist collections with respect to the different ARs were constructed by including binding data to human species only. FLAP models well discriminate “active” (=highly potent) from “inactive” (=weakly potent) AR antagonists, as indicated by enrichment curves, numbers of false positives, and AUC values. For all FLAP modes, model predictivity slightly decreases as follows: A_2BR > A_2AR > A₃R > A₁R antagonists. General performance of FLAP modes in this study is: ligand- > structure- > pharmacophore- based mode. We also compared the FLAP performance with other common ligand- and structure-based fingerprints. Concerning the ligand-based mode, FLAP model performance is superior to ECFP4 and ROCS for all AR subtypes. Although focusing on the early first part of the A_2A, A_2B and A₃ enrichment curves, ECFP4 and ROCS still retain a satisfactory retrieval of actives. FLAP is also superior when comparing the structure-based mode with PLANTS and GOLD. In this study we applied for the first time the novel FLAPPharm tool for pharmacophore generation. Pharmacophore hypotheses, generated with this tool, convincingly match with formerly published data. Finally, we could demonstrate the capability of FLAP models to uncover selectivity aspects although single AR subtype models were not trained for this purpose.

Journal of Computer-Aided Molecular Design published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C8H14O2, Safety of 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics

Vallano, Antoni published the artcileAn update on adenosine A_2A receptors as drug target in Parkinson’s disease, Recommanded Product: 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, the publication is CNS & Neurological Disorders: Drug Targets (2011), 10(6), 659-669, database is CAplus and MEDLINE.

A review. Adenosine receptors are G protein-coupled receptors (GPCRs) that mediate the physiol. functions of adenosine. In the central nervous system adenosine A_2A receptors (A_2ARs) are highly enriched in striatopallidal neurons where they form functional oligomeric complexes with other GPCRs such us the dopamine D₂ receptor (D₂R). Furthermore, it is assumed that the formation of balanced A_2AR/D₂R receptor oligomers are essential for correct striatal function as the allosteric receptor-receptor interactions established within the oligomer are needed for properly sensing adenosine and dopamine. Interestingly, A_2AR activation reduces the affinity of striatal D₂R for dopamine and the blockade of A_2AR with specific antagonists facilitates function of the D₂R. Thus, it may be postulated that A_2AR antagonists are pro-dopaminergic agents. Therefore, A_2AR antagonists will potentially reduce the effects associated with dopamine depletion in Parkinson’s disease (PD). Accordingly, this class of compounds have recently attracted considerable attention as potential therapeutic agents for PD pharmacotherapy as they have shown potential effectiveness in counteracting motor dysfunctions and also displayed neuroprotective and anti-inflammatory effects in animal models of PD. Overall, we provide here an update of the current state of the art of these A_2AR-based approaches that are under clin. study as agents devoted to alleviate PD symptoms.

CNS & Neurological Disorders: Drug Targets published new progress about 377727-87-2. 377727-87-2 belongs to triazoles, auxiliary class GPCR/G Protein,Adenosine Receptor, name is 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine, and the molecular formula is C11H16BNO3, Recommanded Product: 2-(Furan-2-yl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine.

Referemce:
https://en.wikipedia.org/wiki/1,2,3-Triazole,
Triazoles – an overview | ScienceDirect Topics