Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists

Allison L Zulli; Lisa D Aimone; Joanne R Mathiasen; John A Gruner; Rita Raddatz; Edward R Bacon; Robert L Hudkins

doi:10.1016/j.bmcl.2012.02.081

Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2807-10. doi: 10.1016/j.bmcl.2012.02.081. Epub 2012 Mar 2.

Authors

Allison L Zulli¹, Lisa D Aimone, Joanne R Mathiasen, John A Gruner, Rita Raddatz, Edward R Bacon, Robert L Hudkins

Affiliation

¹ Discovery Research, Cephalon, Inc., West Chester, PA 19380, USA. azulli@cephalon.com

PMID: 22450133
DOI: 10.1016/j.bmcl.2012.02.081

Abstract

Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.

MeSH terms

1-Propanol / chemistry
1-Propanol / pharmacology
Animals
Drug Inverse Agonism*
Histamine Agonists* / chemistry
Histamine Agonists* / pharmacology
Humans
Ketones / chemistry*
Ketones / pharmacology
Methylamines / chemistry
Methylamines / pharmacology
Phenols / chemistry
Phenols / pharmacology
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Rats
Sleep Disorders, Circadian Rhythm / drug therapy
Wakefulness / drug effects*

Substances

Histamine Agonists
Ketones
Methylamines
Phenols
Pyrrolidines
phenoxy radical
1-Propanol
methylamine
pyrrolidine