Solubilized phenyl-pyrazole ureas as potent, selective 5-HT2A inverse-agonists and their application as antiplatelet agents

Dosa, Peter I.; Strah-Pleynet, Sonja; Jayakumar, Honnappa; Casper, Martin D.; Decaire, Marc; Xiong, Yifeng; Lehmann, Juerg; Choi, Karoline; Elwell, Katie H.; Wong, Amy; Webb, Robert R.; Adams, John; Ramirez, Juan Ignacio; Richman, Jeremy G.; Thomsen, William J.; Semple, Graeme; Teegarden, Bradley R.

doi:10.1016/j.bmcl.2009.07.073

Cited by 8 publications

(7 citation statements)

References 11 publications

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“…In addition to their impact on the CNS, the 5‐HT 2A receptor is engaged in the regulation of cardiovascular system function. Therefore, phenyl‐pyrazole ureas, selective inverse agonists of this receptor, have found application as antiplatelet agents . Derivatives of butanoyl‐3‐arylthiourea were also examined biochemically as potential cholinesterase (AChE/BuChE) inhibitors, as these two enzymes are involved in the pathological processes of AD .…”

Section: Introductionmentioning

confidence: 99%

G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

Szulczyk

Bielenica

Kędzierska

et al. 2019

Archiv der Pharmazie

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Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT 2A and 5-HT 2C receptors, as well as their functional activities at the 5-HT 1A and D 2 receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT 1A receptor, showing, at the same time, significant selectivity over the studied 5-HT 2 and D 2 receptor subtypes.The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity. K E Y W O R D Sdopamine receptors, inverse agonists, serotonin antagonism, substituent effect

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Section: Introductionmentioning

confidence: 99%

G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

Szulczyk

Bielenica

Kędzierska

et al. 2019

Archiv der Pharmazie

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“…Moreover these compounds also showed improved inhibition of platelet aggregation. 14 Unfortunately, many of these solubilized ureas had suboptimal selectivity profiles and poor pharmacokinetic properties. To further explore the scope of the soluble phenyl-pyrazole scaffold, with a particular goal of improving the pharmacokinetic and pharmaceutical characteristics, the SAR was expanded from ureas to sulfonamides, carbamates, and amides.…”

Section: Introductionmentioning

confidence: 99%

“…We have since reported on modifications to this urea series in which we incorporated amino moieties into the scaffold. The resulting series of phenyl-pyrazole ureas as exemplified by 3 − were significantly more soluble in aqueous solution. Moreover these compounds also showed improved inhibition of platelet aggregation .…”

Section: Introductionmentioning

confidence: 99%

Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

et al. 2010

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Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT(2A) receptor. 5-HT(2A) receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT(2A) receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC(50) = 8.7 nM and had negligible binding affinity for the closely related 5-HT(2B) and 5-HT(2C) receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.

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“…24 The synthesis of 1 proved to be more problematic than expected. Most published syntheses of cabergoline start from cabergolinic acid 2 or its methyl ester 3, shown in Scheme 2 and Scheme 1, respectively.…”

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confidence: 99%

“…We began our efforts to reduce 5-HT 2B activity by replacing the dimethylamino side chain of cabergoline with a less basic morpholine group (compound 1 in Figure ), as a similar change has previously been shown to help reduce activity at 5-HT 2 receptors . The synthesis of 1 proved to be more problematic than expected.…”

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Synthesis of Novel Analogs of Cabergoline: Improving Cardiovascular Safety by Removing 5-HT_2B Receptor Agonism

Dosa

Ward²,

Walters

et al. 2013

ACS Med. Chem. Lett.

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The dopamine agonist cabergoline has been used to treat prolactinomas, Parkinson’s disease, Cushing’s disease and sexual dysfunction. However, its clinical use was severely curtailed when it was found that patients taking cabergoline had an increased risk of developing cardiac-valve regurgitation. This potentially life-threatening condition has been associated with drugs, such as cabergoline, that are 5-HT2B receptor agonists. We prepared analogs of cabergoline and have identified several that have limited or no agonism at the 5-HT2B receptor.

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Solubilized phenyl-pyrazole ureas as potent, selective 5-HT2A inverse-agonists and their application as antiplatelet agents

Cited by 8 publications

References 11 publications

G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

Synthesis of Novel Analogs of Cabergoline: Improving Cardiovascular Safety by Removing 5-HT_2B Receptor Agonism

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Solubilized phenyl-pyrazole ureas as potent, selective 5-HT2A inverse-agonists and their application as antiplatelet agents

Cited by 8 publications

References 11 publications

G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

G protein‐coupled receptor binding and pharmacological evaluation of indole‐derived thiourea compounds

Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

Synthesis of Novel Analogs of Cabergoline: Improving Cardiovascular Safety by Removing 5-HT2B Receptor Agonism

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Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

Synthesis of Novel Analogs of Cabergoline: Improving Cardiovascular Safety by Removing 5-HT_2B Receptor Agonism