4-acyl-1-(4-aminoalkoxyphenyl)-2-ketopiperazines as a novel class of non-brain-penetrant histamine H3 receptor antagonists.
J Med Chem
; 50(26): 6706-17, 2007 Dec 27.
Article
in En
| MEDLINE
| ID: mdl-18052318
ABSTRACT
A series of ketopiperazines were prepared and evaluated for their activity as histamine H 3 antagonists. From investigation of the tertiary basic center in the aminopropyloxyphenyl template, the 2( R)-methylpyrrolidine was identified as the most potent amine. In the more rigid piperidineoxyphenyl template the N-cyclobutyl group was the most potent amine. The 4-fluorobenzyol, 4-cyanobenzoyl, and 2,4-difluorobenzoyl groups provided good pharmacokinetic profiles for the various amides. The PSA and log D values of these compounds suggested low brain penetration. The compounds had very high selectivity over other receptors and did not inhibit hepatic cytochrome P450, indicating low drug-drug interaction potential. Compound 22i was identified as the best compound of this series based on its overall profile of high potency, selectivity, low brain penetration, lack of CYP450 inhibition, high oral bioavailability, and pharmacokinetic properties.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperazines
/
Brain
/
Histamine H3 Antagonists
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2007
Type:
Article
Affiliation country:
United kingdom