Tag: M.W=500-550

Cutler, David L. published the artcileEvaluation of the effects of a high-fat meal on the oral bioavailability of a single dose of preladenant in healthy subjects, Name: 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 Clinical Pharmacology (2012), 52(11), 1698-1703, database is CAplus and MEDLINE.

The aim of this study was to evaluate the effect of food on the oral bioavailability of preladenant, a novel adenosine A_2A receptor antagonist. This open-label, randomized, single-dose, 2-way crossover study evaluated the effects of a high-fat, high-calorie meal on the pharmacokinetics of preladenant and its metabolite (SCH434748) following oral administration of a single 25-mg preladenant capsule to 24 healthy subjects. When administered with food, the time of maximum concentration (T_max) of preladenant was prolonged compared with administration in the fasting state. Whereas T_max was increased from 0.9 h to 2.6 h and maximum concentration (C_max) was decreased (from 212 ng/mL to 128 ng/mL), the extent of absorption (area under the plasma concentration-time curve from time 0 to time of final quantifiable sample, or AUC_[tf]) was unaffected by the meal. Similarly, SCH434748 T_max was prolonged in the fed state, and C_max decreased from 43.7 ng/mL to 28.6 ng/mL. The assessment of AUC_[tf] and area under the plasma concentration-time curve from time 0 to infinity [AUC_[I]] together suggests that the AUC for the metabolite remained unchanged. No serious, significant, or unexpected adverse events occurred. In summary, food delays absorption and reduces peak exposure (C_max) but does not alter the extent of preladenant exposure (AUC). These small changes are unlikely to be of clin. importance. A single 25-mg dose of preladenant is safe and well tolerated in healthy subjects under both fed and fasting conditions.

Journal of Clinical Pharmacology 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, Name: 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

Cutler, D. L. published the artcileSafety, tolerability and pharmacokinetics after single and multiple doses of preladenant (SCH420814) administered in healthy subjects, Application 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 Clinical Pharmacy and Therapeutics (2012), 37(5), 578-587, database is CAplus and MEDLINE.

Summary : What is known and Objective: Preladenant (SCH420814, MK-3814) is a highly selective orally bioavailable non-methylxanthine adenosine 2A (A₂A) receptor antagonist under investigation for the treatment for Parkinson’s disease. This study evaluated the safety, tolerability and pharmacokinetics of preladenant at single and multiple doses for the first time in humans. Methods: These were two randomized, double-blind, placebo-controlled, ascending-dose studies, one evaluating single rising preladenant doses (5-200 mg) compared with placebo and the other evaluating multiple rising preladenant doses (10-200 mg once daily over 10 days) compared with placebo. Safety was the primary end point of both studies. Safety evaluations, phys. examinations, electrocardiograms, vital signs determinations and routine laboratory tests were performed before and at intervals throughout the studies. Blood samples were collected immediately before study drug administration and at various time points after dosing. Pharmacokinetic assessments of plasma preladenant and metabolites SCH434748 and SCH446637 were performed. Results and Discussion: One hundred and eight healthy adult men were randomly assigned in a 3 : 1 ratio to receive oral preladenant or matching placebo capsules under fasting conditions. Preladenant reached peak plasma concentrations in ∼1 h and then declined rapidly. Dose-related increases in exposure were observed up to 100 mg/day; accumulation was negligible at all doses. Transient mild increases in blood pressure occurred within a few hours after preladenant administration; blood pressure changes were neither cumulative nor dose-related nor associated with clin. sequelae. What is new and Conclusion: Preladenant was generally well tolerated up to the maximum dose tested (200 mg/day).

Journal of Clinical Pharmacy and Therapeutics 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 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

Bennett, Kirstie A. published the artcilePharmacology and structure of isolated conformations of the adenosine A_2A receptor define ligand efficacy, Application 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 Molecular Pharmacology (2013), 83(5), 949-958, database is CAplus and MEDLINE.

Using isolated receptor conformations crystal structures of the adenosine A_2A receptor have been solved in active and inactive states. Studying the change in affinity of ligands at these conformations allowed qual. prediction of compound efficacy in vitro in a system-independent manner. Agonist 5′-N-ethylcarboxamidoadenosine displayed a clear preference to bind to the active state receptor; inverse agonists (xanthine amine congener, ZM 241385, SCH 58261, and preladenant) bound preferentially to the inactive state, whereas neutral antagonists (theophylline, caffeine, and istradefylline) demonstrated equal affinity for active and inactive states. Ligand docking into the known crystal structures of the A_2A receptor rationalized the pharmacol. observed; inverse agonists, unlike neutral antagonists, cannot be accommodated within the agonist-binding site of the receptor. The availability of isolated receptor conformations opens the door to the concept of “reverse pharmacol.” whereby the functional pharmacol. of ligands can be characterized in a system-independent manner by their affinity for a pair (or set) of G protein-coupled receptor conformations.

Molecular Pharmacology 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 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

Cutler, David L. published the artcileEvaluation of the effects of a high-fat meal on the oral bioavailability of a single dose of preladenant in healthy subjects, Name: 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 Clinical Pharmacology (2012), 52(11), 1698-1703, database is CAplus and MEDLINE.

The aim of this study was to evaluate the effect of food on the oral bioavailability of preladenant, a novel adenosine A_2A receptor antagonist. This open-label, randomized, single-dose, 2-way crossover study evaluated the effects of a high-fat, high-calorie meal on the pharmacokinetics of preladenant and its metabolite (SCH434748) following oral administration of a single 25-mg preladenant capsule to 24 healthy subjects. When administered with food, the time of maximum concentration (T_max) of preladenant was prolonged compared with administration in the fasting state. Whereas T_max was increased from 0.9 h to 2.6 h and maximum concentration (C_max) was decreased (from 212 ng/mL to 128 ng/mL), the extent of absorption (area under the plasma concentration-time curve from time 0 to time of final quantifiable sample, or AUC_[tf]) was unaffected by the meal. Similarly, SCH434748 T_max was prolonged in the fed state, and C_max decreased from 43.7 ng/mL to 28.6 ng/mL. The assessment of AUC_[tf] and area under the plasma concentration-time curve from time 0 to infinity [AUC_[I]] together suggests that the AUC for the metabolite remained unchanged. No serious, significant, or unexpected adverse events occurred. In summary, food delays absorption and reduces peak exposure (C_max) but does not alter the extent of preladenant exposure (AUC). These small changes are unlikely to be of clin. importance. A single 25-mg dose of preladenant is safe and well tolerated in healthy subjects under both fed and fasting conditions.

Journal of Clinical Pharmacology 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, Name: 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

Cutler, D. L. published the artcileSafety, tolerability and pharmacokinetics after single and multiple doses of preladenant (SCH420814) administered in healthy subjects, Application 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 Clinical Pharmacy and Therapeutics (2012), 37(5), 578-587, database is CAplus and MEDLINE.

Summary : What is known and Objective: Preladenant (SCH420814, MK-3814) is a highly selective orally bioavailable non-methylxanthine adenosine 2A (A₂A) receptor antagonist under investigation for the treatment for Parkinson’s disease. This study evaluated the safety, tolerability and pharmacokinetics of preladenant at single and multiple doses for the first time in humans. Methods: These were two randomized, double-blind, placebo-controlled, ascending-dose studies, one evaluating single rising preladenant doses (5-200 mg) compared with placebo and the other evaluating multiple rising preladenant doses (10-200 mg once daily over 10 days) compared with placebo. Safety was the primary end point of both studies. Safety evaluations, phys. examinations, electrocardiograms, vital signs determinations and routine laboratory tests were performed before and at intervals throughout the studies. Blood samples were collected immediately before study drug administration and at various time points after dosing. Pharmacokinetic assessments of plasma preladenant and metabolites SCH434748 and SCH446637 were performed. Results and Discussion: One hundred and eight healthy adult men were randomly assigned in a 3 : 1 ratio to receive oral preladenant or matching placebo capsules under fasting conditions. Preladenant reached peak plasma concentrations in ∼1 h and then declined rapidly. Dose-related increases in exposure were observed up to 100 mg/day; accumulation was negligible at all doses. Transient mild increases in blood pressure occurred within a few hours after preladenant administration; blood pressure changes were neither cumulative nor dose-related nor associated with clin. sequelae. What is new and Conclusion: Preladenant was generally well tolerated up to the maximum dose tested (200 mg/day).

Journal of Clinical Pharmacy and Therapeutics 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 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

Bennett, Kirstie A. published the artcilePharmacology and structure of isolated conformations of the adenosine A_2A receptor define ligand efficacy, Application 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 Molecular Pharmacology (2013), 83(5), 949-958, database is CAplus and MEDLINE.

Using isolated receptor conformations crystal structures of the adenosine A_2A receptor have been solved in active and inactive states. Studying the change in affinity of ligands at these conformations allowed qual. prediction of compound efficacy in vitro in a system-independent manner. Agonist 5′-N-ethylcarboxamidoadenosine displayed a clear preference to bind to the active state receptor; inverse agonists (xanthine amine congener, ZM 241385, SCH 58261, and preladenant) bound preferentially to the inactive state, whereas neutral antagonists (theophylline, caffeine, and istradefylline) demonstrated equal affinity for active and inactive states. Ligand docking into the known crystal structures of the A_2A receptor rationalized the pharmacol. observed; inverse agonists, unlike neutral antagonists, cannot be accommodated within the agonist-binding site of the receptor. The availability of isolated receptor conformations opens the door to the concept of “reverse pharmacol.” whereby the functional pharmacol. of ligands can be characterized in a system-independent manner by their affinity for a pair (or set) of G protein-coupled receptor conformations.

Molecular Pharmacology 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 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

Zhang, Li-Kang published the artcileCharacterization of major degradation products of an adenosine A_2A receptor antagonist under stressed conditions by LC-MS and FT tandem MS analysis, SDS of cas: 377727-87-2, the publication is Journal of Mass Spectrometry (2010), 45(2), 146-156, database is CAplus and MEDLINE.

Parkinson’s disease (PD) is a very serious neurol. disorder, and current methods of treatment fail to achieve long-term control. SCH 420814 is a potent, selective and orally active adenosine A_2A receptor antagonist discovered by Schering-Plough. Stability testing provides evidence of the quality of a bulk drug when exposed to the influence of environmental factors. Understanding the drug degradation profiles is critical to the safety and potency assessment of the drug candidate for clin. trials. As a result, identification of degradation products has taken an important role in drug development process. In this study, a rapid and sensitive method was developed for the structural determination of the degradation products of SCH 420814 formed under different forced conditions. The study utilizes a combination of liquid chromatog.-tandem-mass spectrometry (LC-MS/MS) and Fourier Transform (FT) MS techniques to obtain complementary information for structure elucidation of the unknowns. This combination approach has significant impact on degradation product identification. A total of ten degradation products of SCH 420814 were characterized using the developed method. Copyright © 2009 John Wiley & Sons, Ltd.

Journal of Mass Spectrometry 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 C10H9IO4, SDS of cas: 377727-87-2.

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

Saini, Anjali published the artcileAdenosine receptor antagonists: Recent advances and therapeutic perspective, 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 European Journal of Medicinal Chemistry (2022), 113907, database is CAplus and MEDLINE.

A review. Adenosine is an endogenous purine-based nucleoside expressed nearly in all body tissues. It regulates various body functions by activating four G-protein coupled receptors, A1, A2A, A2B, and A3. These receptors are widely acknowledged as drug targets for treating different neurol., metabolic, and inflammatory diseases. Although numerous adenosine receptor inhibitors have been developed worldwide, achieving target selectivity is still a big hurdle in drug development. However, the identification of specific radioligands-based affinity assay, fluorescent ligands, and MS-based ligand assay have contributed to the development of selective and potent adenosine ligands. In recent years various small heterocyclic-based mols. have shown some promising results. Istradefylline has been approved for treating Parkinson’s in Japan, while preladenant, tozadenant, CVT-6883, MRS-1523, and many more are under different phases of clin. development. The present review is focused on the quest to develop potent and selective adenosine inhibitors from 2013 to early 2021 by various research groups. The review also highlights their biol. activity, selectivity, structure-activity relationship, mol. docking, and mechanistic studies. A special emphsesis on drug designing strategies has been also given the manuscript. The comprehensive compilation of research work carried out in the field will provide inevitable scope for designing and developing novel adenosine inhibitors with improved selectivity and efficacy.

European 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 C25H29N9O3, 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

Salem, Haitham published the artcileRevisiting Antipsychotic-induced Akathisia: Current Issues and Prospective Challenges, Category: triazoles, the publication is Current Neuropharmacology (2017), 15(5), 789-798, database is CAplus and MEDLINE.

A review. Background: Akathisia continues to be a significant challenge in current neurol. and psychiatric practice. Prompt and accurate detection is often difficult and there is a lack of consensus concerning the neurobiol. basis of akathisia. No definitive treatment has been established for akathisia despite numerous preclin. and clin. studies. Method: We reviewed antipsychotic-induced akathisia including its clin. presentation, proposed underlying pathophysiol., current and under investigation therapeutic strategies. Conclusion: Despite the initial promise that second generation antipsychotics would be devoid of akathisia effects, this has not been confirmed. Currently, there are limited therapeutic options for the clin. practice and the evidence supporting the most widely used treatments (beta blockers, anticholinergic drugs) is still absent or inconsistent.

Current Neuropharmacology 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, Category: triazoles.

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

Garantziotis, Panagiotis published the artcileMolecular taxonomy of systemic lupus erythematosus through data-driven patient stratification: molecular endotypes and cluster-tailored drugs, Application In Synthesis of 377727-87-2, the publication is Frontiers in Immunology (2022), 860726, database is CAplus and MEDLINE.

Treatment of Systemic Lupus Erythematosus (SLE) is characterized by a largely empirical approach and relative paucity of novel compound development. We sought to stratify SLE patients based on their mol. phenotype and identify putative therapeutic compounds for each mol. fingerprint. By the use of whole blood RNA-seq data from 120 SLE patients, and in a data-driven, clin. unbiased manner, we established modules of commonly regulated genes (mol. endotypes) and re-stratified patients through hierarchical clustering. Disease activity and severity were assessed using SLEDAI-2K and Lupus Severity Index, resp. Through an in silico drug prediction pipeline, we investigated drugs currently in use, tested in lupus clin. trials, and listed in the iLINCS prediction databases, for their ability to reverse the gene expression signatures in each mol. endotype. Drug repurposing anal. was also performed to identify perturbagens that counteract group-specific SLE signatures. Mol. taxonomy identified five lupus endotypes, each characterized by a unique gene module enrichment pattern. Neutrophilic signature group consisted primarily of patients with active lupus nephritis, while the B-cell expression group included patients with constitutional features. Patients with moderate severity and serol. activity exhibited a signature enriched for metabolic processes. Mild disease was distributed in two groups, exhibiting enhanced basic cellular functions, myelopoiesis, and autophagy. Bortezomib was predicted to reverse disturbances in the “neutrophilic” cluster, azathioprine and ixazomib in the “B-cell” cluster, and fostamatinib in the “metabolic” patient subgroup. The clin. spectrum of SLE encompasses distinct mol. endotypes, each defined by unique pathophysiol. aberrancies potentially reversible by distinct compounds

Frontiers in Immunology 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