Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain

Brian Dyck; Junko Tamiya; Florence Jovic; Rebecca R Pick; Margaret J Bradbury; Julie O'Brien; Jenny Wen; Michael Johns; Ajay Madan; Beth A Fleck; Alan C Foster; Binfeng Li; Mingzhu Zhang; Joe A Tran; Troy Vickers; Jonathan Grey; John Saunders; Chen Chen

doi:10.1021/jm8009537

Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain

J Med Chem. 2008 Nov 27;51(22):7265-72. doi: 10.1021/jm8009537.

Authors

Brian Dyck¹, Junko Tamiya, Florence Jovic, Rebecca R Pick, Margaret J Bradbury, Julie O'Brien, Jenny Wen, Michael Johns, Ajay Madan, Beth A Fleck, Alan C Foster, Binfeng Li, Mingzhu Zhang, Joe A Tran, Troy Vickers, Jonathan Grey, John Saunders, Chen Chen

Affiliation

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

PMID: 18954038
DOI: 10.1021/jm8009537

Abstract

Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.

MeSH terms

Administration, Oral
Animals
Biological Availability
Caco-2 Cells
Crystallography, X-Ray
Cyclopropanes / chemistry
Cyclopropanes / metabolism
Cyclopropanes / pharmacokinetics
Cyclopropanes / pharmacology*
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Design
Humans
Male
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Milnacipran
Models, Molecular
Molecular Structure
Molecular Weight
Neuralgia / drug therapy*
Neuralgia / pathology
Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Pain Measurement / drug effects*
Rats
Rats, Sprague-Dawley
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / metabolism
Selective Serotonin Reuptake Inhibitors / pharmacokinetics
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin Plasma Membrane Transport Proteins / metabolism*
Spinal Nerves / pathology
Spinal Nerves / surgery
Stereoisomerism*
Structure-Activity Relationship

Substances

Cyclopropanes
Norepinephrine Plasma Membrane Transport Proteins
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors
Milnacipran