Diamine-based human histamine H3 receptor antagonists: (4-Aminobutyn-1-yl)benzylamines

Dvorak, Curt A.; Apodaca, Richard; Xiao, Wei; Jablonowski, Jill A.; Bonaventure, Pascal; Dugovic, Christine; Shelton, Jonathan; Lord, Brian; Miller, Kirsten L.; Dvorak, Lisa; Lovenberg, Timothy W.; Carruthers, Nicholas I.

doi:10.1016/j.ejmech.2009.04.049

Cited by 12 publications

(4 citation statements)

References 27 publications

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“…For example, the substitution of the piperidine ring with a morpholine in a series of (4aminobutyn-1-yl)benzylamines H 3 antagonists results in the improvement of potency and CNS druggability, as shown by JNJ-10181457 possessing a shorter plasma half-life and a higher ability to penetrate the BBB, with brain concentration values that roughly parallel those found in plasma (Figure 6). 62 Similarly, morpholine is contained in different mGlu2 (metabotropic Glutamate receptor 2) negative allosteric modulators (NAM) to increase their pharmacokinetic properties. mGlu2 is another metabotropic receptor that is broadly expressed in the CNS and represents an important therapeutic target for mood disorders (anxiety, depression, schizophrenia, addiction), as well as for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD).…”

Section: ■ Biological Activity Of Morpholine Derivatives In Mood Diso...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 Diso...mentioning

confidence: 99%

Occurrence of Morpholine in Central Nervous System Drug Discovery

Lenci

Calugi

Trabocchi

2021

ACS Chem. Neurosci.

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“…In an attempt to increase its affinity but also to reduce the undesired high brain residence time of 103 , Johnson & Johnson developed JNJ‐10181457 ( 104 ) which possesses high affinity ( K i = 1.2 nM) and more than 10 000 fold selectivity for H 3 over H 1 and H 4 . In the SAR studies that were conducted, meta‐substitution of the central phenyl ring provided the most potent antagonists, while various substituents proved to be more potent than the morpholine substituent of 104 .…”

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

187

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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“…To demonstrate the synthetic utility of the TH of pyridinium salts, a gram-scale synthesis of 4a , an intermediate for the synthesis of paroxetine 17 and strychnocarpine derivatives, 18 was performed (Scheme 3). Furthermore, 4r and 4s , the key intermediates for the synthesis of HDAC inhibitor 7 19 and histamine H 3 receptor 8 , 20 respectively, were obtained in good yields under the standard reaction conditions.…”

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confidence: 96%