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Bioorg Med Chem Lett. 2012 Jan 15;22(2):1073-7. doi: 10.1016/j.bmcl.2011.11.118. Epub 2011 Dec 4.

Synthesis and structure-activity relationship of 5-pyridazin-3-one phenoxypiperidines as potent, selective histamine H(3) receptor inverse agonists.

Author information

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

Abstract

Optimization of the R(2) and R(6) positions of (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2a with constrained phenoxypiperidines led to the identification of 5-[4-(cyclobutyl-piperidin-4-yloxy)-phenyl]-6-methyl-2H-pyridazin-3-one 8b as a potent, selective histamine H(3) receptor antagonist with favorable pharmacokinetic properties. Compound 8b had an excellent safety genotoxocity profile for a CNS-active compound in the Ames and micronucleus tests, also displayed potent H(3)R antagonist activity in the brain in the rat dipsogenia model and robust wake activity in the rat EEG/EMG model.

PMID:
22197136
DOI:
10.1016/j.bmcl.2011.11.118
[Indexed for MEDLINE]

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