944284-86-0Relevant articles and documents
N-(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability
Ferlenghi, Francesca,Mari, Michele,Gobbi, Gabriella,Elisi, Gian Marco,Mor, Marco,Rivara, Silvia,Vacondio, Federica,Bartolucci, Silvia,Bedini, Annalida,Fanini, Fabiola,Spadoni, Gilberto
, p. 3071 - 3082 (2021/08/06)
The MT2-selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT1 and MT2 binding affinities. Introduction of a m-hydroxymethyl substituent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a N-methyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation.
NOVEL MELATONIN LIGANDS HAVING ANTIDEPRESSANT ACTIVITY AS WELL AS SLEEP INDUCING PROPERTIES
-
Page/Page column 28, (2010/11/28)
Novel melatonin ligands of Formula (I) or pharmaceutically acceptable salts thereof wherein: n is 1 or 2; m is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; v is 2 or 3; A is aryl or heteroaryl; Z is O, S or NR8;Y is selected from the group consisting of hydrogen, aryl, heteroaryl, CrC6 alkyl, C3-C6 cycloalkyl, and R is selected from the group consisting of hydrogen, hydroxyl, -OCF3, CF3, C1-C8 alkyl, C1C8 alkyloxy, C1C8 alkylthio, halogen and -Z-(CH2)P-A; R1 is selected from the group consisting of C1C4 alkyl, C3-C6 cycloalkyl, CF3, hydroxy-substituted C1C4 alkyl, hydroxy-substituted C3-C6 cycloalkyl, and NHR5, wherein R5 is C1C3 alkyl or C3-C6 cycloalkyl; R2 is selected from the group consisting of: hydrogen, C1C4 alkyl, C1C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; R3 is selected from the group consisting of hydrogen, C1C4 alkyl, C1C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; R and R3 may be connected together to form an -0-(CH2)v bridge representing with the carbon atoms to which they are attached a 5- or 6-membered heterocyclic ring system; R4 is selected from the group consisting of hydrogen, C1C4 alkyl, C1C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; R6 is selected from the group consisting of hydrogen and C1C6 alkyl; R7 is selected from the group consisting of hydrogen, C1C4 alkyl, C1C4 alkyloxy, OCF3, CF3, hydroxyl, and halogen; and R8 is selected from the group consisting of hydrogen and C1C4 alkyl.
