Pyrrolidine and piperidine analogues of SC-57461A as potent, orally active inhibitors of leukotriene A(4) hydrolase.
The synthesis and biological evaluation of a series of functionalized pyrrolidine- and piperidine-containing analogues of our lead LTA(4) hydrolase inhibitor, SC-57461A, is described. A number of compounds showed excellent potency in our in vitro screens and several demonstrated good oral activity in a mouse ex vivo assay. These efforts led to the identification of SC-56938 (14) as a potent, orally active inhibitor of LTA(4) hydrolase.
Penning
Thomas D
TD
Department of Medicinal Chemistry, Pharmacia Corporation, Skokie, IL 60077, USA. thomas.d.penning@pharmacia.com
Chandrakumar
Nizal S
NS
Desai
Bipin N
BN
Djuric
Stevan W
SW
Gasiecki
Alan F
AF
Liang
Chi-Dean
CD
Miyashiro
Julie M
JM
Russell
Mark A
MA
Askonas
Leslie J
LJ
Gierse
James K
JK
Harding
Elizabeth I
EI
Highkin
Maureen K
MK
Kachur
James F
JF
Kim
Suzanne H
SH
Villani-Price
Doreen
D
Pyla
E Yvonne
EY
Ghoreishi-Haack
Nayereh S
NS
Smith
Walter G
WG
D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000737:chemistry*
D004791:Enzyme Inhibitors; D010880:Piperidines; D011759:Pyrrolidines; C104311:SC 57461; C474036:SC56938; D015091:beta-Alanine; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase