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.
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Timothy A
TA
Lewis
Michelle A
MA
Young
Mark P
MP
Arrington
Lynn
L
Bayless
Xiong
X
Cai
Philippe
P
Collart
Joseph B
JB
Eckman
James L
JL
Ellis
Doina G
DG
Ene
Lyn
L
Libertine
Jean-Marie
JM
Nicolas
Ralph T
RT
Scannell
Bruce F
BF
Wels
Karen
K
Wenberg
Donna M
DM
Wypij
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