4-acyl-1-(4-aminoalkoxyphenyl)-2-ketopiperazines as a novel class of non-brain-penetrant histamine H3 receptor antagonists.
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.
Procopiou
Panayiotis A
PA
Department of Chemistry, GlaxoSmithKline Medicines REsearch Centre, Hertfordshire, UK. pan.a.procopiou@gsk.com
Ancliff
Rachael A
RA
Bamford
Mark J
MJ
Browning
Christopher
C
Connor
Helen
H
Davies
Susannah
S
Fogden
Yvonne C
YC
Hodgson
Simon T
ST
Holmes
Duncan S
DS
Looker
Brian E
BE
Morriss
Karen M L
KM
Parr
Christopher A
CA
Pickup
Elizabeth A
EA
Sehmi
Sanjeet S
SS
White
Gemma V
GV
Watts
Clarissa J
CJ
Wilson
David M
DM
Woodrow
Michael D
MD
D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D054828:Histamine H3 Antagonists; D007527:Isoenzymes; D010879:Piperazines; D003577:Cytochrome P-450 Enzyme System