Synthesis and evaluation of pyridazinone-phenethylamine derivatives as selective and orally bioavailable histamine H3 receptor antagonists with robust wake-promoting activity

Reddeppa Reddy Dandu; John A Gruner; Joanne R Mathiasen; Lisa D Aimone; Greg Hostetler; Caitlyn Benfield; Robert J Bendesky; Val R Marcy; Rita Raddatz; Robert L Hudkins

doi:10.1016/j.bmcl.2011.08.104

Synthesis and evaluation of pyridazinone-phenethylamine derivatives as selective and orally bioavailable histamine H3 receptor antagonists with robust wake-promoting activity

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6362-5. doi: 10.1016/j.bmcl.2011.08.104. Epub 2011 Sep 1.

Authors

Reddeppa Reddy Dandu¹, John A Gruner, Joanne R Mathiasen, Lisa D Aimone, Greg Hostetler, Caitlyn Benfield, Robert J Bendesky, Val R Marcy, Rita Raddatz, Robert L Hudkins

Affiliation

¹ Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rdandu@cephalon.com

PMID: 21944855
DOI: 10.1016/j.bmcl.2011.08.104

Abstract

A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H(3)R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H(3)R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model.

MeSH terms

Administration, Oral
Animals
Biological Availability
Electroencephalography
Electromyography
Histamine H3 Antagonists / chemical synthesis*
Histamine H3 Antagonists / pharmacokinetics
Histamine H3 Antagonists / pharmacology*
Humans
Rats
Structure-Activity Relationship

Substances

Histamine H3 Antagonists