Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain

Robert J Altenbach; Lawrence A Black; Marina I Strakhova; Arlene M Manelli; Tracy L Carr; Kennan C Marsh; Jill M Wetter; Erica J Wensink; Gin C Hsieh; Prisca Honore; Tiffany Runyan Garrison; Jorge D Brioni; Marlon D Cowart

doi:10.1021/jm100666w

Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain

J Med Chem. 2010 Nov 11;53(21):7869-73. doi: 10.1021/jm100666w.

Authors

Robert J Altenbach¹, Lawrence A Black, Marina I Strakhova, Arlene M Manelli, Tracy L Carr, Kennan C Marsh, Jill M Wetter, Erica J Wensink, Gin C Hsieh, Prisca Honore, Tiffany Runyan Garrison, Jorge D Brioni, Marlon D Cowart

Affiliation

¹ Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, United States. [email protected]

PMID: 20945906
DOI: 10.1021/jm100666w

Abstract

A series of compounds was designed as dual inhibitors of the H(3) receptor and the norepinephrine transporter. Compound 5 (rNET K(i) = 14 nM; rH(3)R K(i) = 37 nM) was found to be efficacious in a rat model of osteoarthritic pain.

MeSH terms

Animals
Histamine H3 Antagonists / chemical synthesis*
Histamine H3 Antagonists / pharmacokinetics
Histamine H3 Antagonists / pharmacology
Naphthols / chemical synthesis*
Naphthols / pharmacokinetics
Naphthols / pharmacology
Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
Osteoarthritis / drug therapy
Pain / drug therapy*
Pyrrolidines / chemical synthesis*
Pyrrolidines / pharmacokinetics
Pyrrolidines / pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol
Histamine H3 Antagonists
Naphthols
Norepinephrine Plasma Membrane Transport Proteins
Pyrrolidines