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

Xiong, Yifeng; Teegarden, Bradley R.; Choi, Jin-Sun Karoline; Strah-Pleynet, Sonja; Decaire, Marc; Jayakumar, Honnappa; Dosa, Peter I.; Casper, Martin D.; Pham, Lan; Feichtinger, Konrad; Ullman, Brett R.; Adams, John; Yuskin, Diane; Frazer, John; Morgan, Michael; Sadeque, Abu; Chen, Weichao; Webb, Robert R.; Connolly, Daniel T.; Semple, Graeme; Al-Shamma, Hussien

doi:10.1021/jm100044a

Cited by 14 publications

(11 citation statements)

References 19 publications

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“…In addition, temanogrel (APD791) is a potent inverse agonist of the serotonin receptor, in which the N -morpholinoethyl moiety provides selectivity for the 5-HT 2A isoform versus the 5-HT 2B and 5-HT 2c receptors (Figure ). As 5-HT 2A is involved in the reduction of thrombus formation, by inhibiting the inositol phosphate accumulation, temanogrel entered Phase I clinical trial as a potential antiplatelet agent. , …”

Section: Biological Activity Of Morpholine Derivatives In Mood Disord...mentioning

confidence: 99%

Occurrence of Morpholine in Central Nervous System Drug Discovery

Lenci

Calugi

Trabocchi

2021

ACS Chem. Neurosci.

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Developing drugs for the central nervous system (CNS) requires fine chemical modifications, as a strict balance between size and lipophilicity is necessary to improve the permeability through the blood-brain barrier (BBB). In this context, morpholine and its analogues represent valuable heterocycles, due to their conformational and physicochemical properties. In fact, the presence of a weak basic nitrogen atom and of an oxygen atom at the opposite position provides a peculiar pK a value and a flexible conformation to the ring, thus allowing it to take part in several lipophilic−hydrophilic interactions, and to improve blood solubility and brain permeability of the overall structure. In CNS-active compounds, morpholines are used (1) to enhance the potency through molecular interactions, (2) to act as a scaffold directing the appendages in the correct position, and (3) to modulate pharmacokinetic/ pharmacodynamic (PK/PD) properties. In this perspective, selected morpholinecontaining CNS drug candidates are discussed to reveal the active pharmacophores accountable for the (1) modulation of receptors involved in mood disorders and pain, (2) bioactivity toward enzymes and receptors responsible for neurodegenerative diseases, and (3) inhibition of enzymes involved in the pathology of CNS tumors. The medicinal chemistry/pharmacological activity of morpholine derivatives is discussed, in the effort to highlight the importance of morpholine ring interactions in the active site of different targets, particularly reporting binding features retrieved from PDB data, when available.

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Section: Biological Activity Of Morpholine Derivatives In Mood Disord...mentioning

confidence: 99%

Occurrence of Morpholine in Central Nervous System Drug Discovery

Lenci

Calugi

Trabocchi

2021

ACS Chem. Neurosci.

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“…An interesting example of morpholine containing active molecule is the antithrombotic agent APD‐791 ( 83 ) (Figure ) . Compound 83 is a potent 5‐HT 2A inverse agonist ( K i = 4.9 nM) with selectivity over the related 5‐HT 2B and 5‐HT 2C as well as a panel of 70 other GPCRs.…”

Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

171

114

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Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

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“…Other 5HT 2A receptor antagonists have been available in the past that also showed ef icacy in acute arterial thrombosis, e.g., ketanserin [26] ritanserin [9], LU 49938 [27], MDL11,939, and LY53,857 [21], MDL 28,133A [28], DV-7028 [29], AT-1015 [30,31], APD791 [32][33][34]. The 5HT 2A antagonists presently available are Th001 (Arteclere TM ), a speci ic platelet receptor antagonist and nefazodone [35], an antidepressant now taken off the market with non-platelet effects and an unknown effect on thrombosis.…”

Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Inmentioning

confidence: 99%

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

Mi¹

2017

J Hematol Clin Res

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An enquiry into the lack of attention awarded to serotonin antagonism in the treatment of arterial thrombosis revealed that the mode of action of serotonin and its platelet receptor antagonists was an action upon thrombus growth, and not, as with other anti-platelet drugs upon the initiation of thrombosis. This lack of effect could explain why this approach has been considered not to be effective. However under conditions of arterial stenosis in which there is platelet activation by increased shear stress, and during the growth phase of arterial thrombi, serotonin 5HT 2A antagonism has been demonstrated to have great potentcy in dispersing thrombotic obstruction to blood fl ow. This mode of action, the lack of participation of serotonin in haemostasis, and the absence of serotonin in wounds accounts for the proven lack of effect of effect of pure specifi c 5HT 2A antagonists (i.e., not those with other actions) on operative bleeding and skin bleeding times. This lack of effect on haemostasis solves the dosing problem encountered with other anti-thrombotic drugs, with which drug concentration cannot be controlled with single fi xed doses, leading to the association between increased antithrombotic effi cacy and increased bleeding complications. Thus 5HT 2A antagonism appears to be the preferred approach, from the point of view of safety and lack of bleeding risk; this consideration applies particularly to thrombosis therapy in the context of traumatic accidents, surgical operations and invasive procedures such as angioplasty.

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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

Cited by 14 publications

References 19 publications

Occurrence of Morpholine in Central Nervous System Drug Discovery

Occurrence of Morpholine in Central Nervous System Drug Discovery

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

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