Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors

Chen Chen; Brian Dyck; Beth A Fleck; Alan C Foster; Jonathan Grey; Florence Jovic; Michael Mesleh; Kasey Phan; Junko Tamiya; Troy Vickers; Mingzhu Zhang

doi:10.1016/j.bmcl.2008.01.011

Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors

Bioorg Med Chem Lett. 2008 Feb 15;18(4):1346-9. doi: 10.1016/j.bmcl.2008.01.011. Epub 2008 Jan 9.

Authors

Chen Chen¹, Brian Dyck, Beth A Fleck, Alan C Foster, Jonathan Grey, Florence Jovic, Michael Mesleh, Kasey Phan, Junko Tamiya, Troy Vickers, Mingzhu Zhang

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Bioscience, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.

PMID: 18207394
DOI: 10.1016/j.bmcl.2008.01.011

Abstract

Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.

MeSH terms

Acetamides / chemistry
Acetamides / pharmacology
Alkylation
Amides / chemistry
Amides / pharmacology
Cyclopropanes / chemistry*
Cyclopropanes / pharmacology*
Indoles / chemistry
Indoles / pharmacology
Milnacipran
Models, Molecular
Molecular Conformation
Nuclear Magnetic Resonance, Biomolecular
Stereoisomerism
Structure-Activity Relationship
Vesicular Monoamine Transport Proteins / antagonists & inhibitors*
Vesicular Monoamine Transport Proteins / chemistry

Substances

Acetamides
Amides
Cyclopropanes
Indoles
Vesicular Monoamine Transport Proteins
indoline
Milnacipran