Discovery of novel and potent aryl diamines as leukotriene A4 hydrolase inhibitors.
The synthesis and biological evaluation of a series of aryl diamines as inhibitors of LTA(4)-h inhibitors are described. The optimization which led to the identification of the optimal para-substitution on the diphenyl ether moiety and diamine spacer is discussed. The resulting compounds such as 3l have excellent enzyme and cellular potency as well as desirable pharmacokinetic properties.
Khim
Seock-Kyu
SK
Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA.
Bauman
John
J
Evans
Jarred
J
Freeman
Beverly
B
King
Beverly
B
Kirkland
Thomas
T
Kochanny
Monica
M
Lentz
Dao
D
Liang
Amy
A
Mendoza
Lisa
L
Phillips
Gary
G
Tseng
Jih-Lie
JL
Wei
Robert G
RG
Ye
Hong
H
Yu
Limei
L
Parkinson
John
J
Guilford
William J
WJ
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D051381:Rats
D000893:Anti-Inflammatory Agents; D003959:Diamines; D004791:Enzyme Inhibitors; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase