Cetirizine and loratadine-based antihistamines with 5-lipoxygenase inhibitory activity.
A series of compounds possessing both H(1) histamine receptor antagonist and 5-lipoxygenase (5-LO) inhibitory activities was synthesized. The H(1)-binding scaffolds of cetirizine, efletirizine, and loratadine were linked to a lipophilic N-hydroxyurea, the 5-LO inhibiting moiety of zileuton. Both activities were observed in vivo, as was increased CYP3A4 inhibition compared to their respective single-function drugs. Selected analogs in the series were shown to be orally active in guinea pig models.
Lewis
Timothy A
TA
UCB Research, 840 Memorial Drive, Cambridge, MA 02139, USA. timlewis1201@comcast.net
Young
Michelle A
MA
Arrington
Mark P
MP
Bayless
Lynn
L
Cai
Xiong
X
Collart
Philippe
P
Eckman
Joseph B
JB
Ellis
James L
JL
Ene
Doina G
DG
Libertine
Lyn
L
Nicolas
Jean-Marie
JM
Scannell
Ralph T
RT
Wels
Bruce F
BF
Wenberg
Karen
K
Wypij
Donna M
DM
D000818:Animals; D017332:Cetirizine / Q000737:chemistry* / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016859:Lipoxygenase Inhibitors; D017336:Loratadine / Q000737:chemistry* / Q000493:pharmacokinetics; D023421:Models, Animal; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D006634:Histamine H1 Antagonists; D016859:Lipoxygenase Inhibitors; D017336:Loratadine; D017332:Cetirizine