Synthesis of potent leukotriene A(4) hydrolase inhibitors. Identification of 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid.
Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of a number of diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention in these disease states, since the action of this enzyme is the rate-limiting step in the production of LTB(4). Our previous efforts focused on the exploration of a series of analogues related to screening hit SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) and resulted in the identification of potent, orally active inhibitors such as 2. Additional structure-activity relationship studies around this structural class resulted in the identification of a series of alpha-, beta-, and gamma-amino acid analogues that are potent inhibitors of the LTA(4) hydrolase enzyme and demonstrated good oral activity in a mouse ex vivo whole blood LTB(4) production assay. The efforts leading to the identification of clinical candidate SC-57461A (8d, 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid) are described.
Penning
Thomas D
TD
Department of Medicinal Chemistry, Pharmacia Corporation, 4901 Searle Parkway, Skokie, IL 60077, USA. thomas.d.penning@pharmacia.com
Russell
Mark A
MA
Chen
Barbara B
BB
Chen
Helen Y
HY
Liang
Chi-Dean
CD
Mahoney
Matthew W
MW
Malecha
James W
JW
Miyashiro
Julie M
JM
Yu
Stella S
SS
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 / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D017572:Leukotriene A4 / Q000096:biosynthesis / Q000097:blood; D051379:Mice; D013329:Structure-Activity Relationship; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D017572:Leukotriene A4; C104311:SC 57461; D015091:beta-Alanine; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase