Development of substituted N-[3-(3-methoxylphenyl)propyl] amides as MT(2)-selective melatonin agonists: improving metabolic stability.

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Hu Y, Zhu J, Chan KH, Wong YH

Development of substituted N-[3-(3-methoxylphenyl)propyl] amides as MT(2)-selective melatonin agonists: improving metabolic stability.

Bioorg Med Chem. 2013 Jan 15;21(2):547-52. doi: 10.1016/j.bmc.2012.10.060. Epub 2012 Nov 20.

PubMed ID

23228808 [ View in PubMed

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Abstract

A series of novel and selective N-[3-(6-benzyloxy-3-methoxyphenyl)propyl] amides has recently been shown to possess sub-nanomolar range binding affinity to the type 2 melatonin receptor (MT(2)). Pharmacokinetics studies suggested that these compounds were subject to vigorous CYP450-mediated metabolism, resulting in a series of metabolites with significantly decreased or diminished binding affinities toward MT(2) receptor. The ether bonds were found to be the major positions susceptible to metabolism. In this study, the benzyl ether bond was either removed or replaced with a carbon-carbon bond in an attempt to improve metabolic stability and enhance their resistance towards phase I oxidation. The synthesis, receptor binding affinity, intrinsic potency and metabolic stability of modified structures are reported in this article. By removal or replacement of metabolic labile ether linkerage with carbon linkers, a novel compound was identified with good potency and MT(2) selectivity, and with increased metabolic stability.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Melatonin	Melatonin receptor type 1A	Ki (nM)	0.296	N/A	N/A	Details
Melatonin	Melatonin receptor type 1B	Ki (nM)	0.429	N/A	N/A	Details