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.
Department of Medicinal Chemistry, Pharmacia Corporation, 4901 Searle Parkway, Skokie, IL 60077, USA. thomas.d.penning@pharmacia.com
Thomas D
TD
Penning
Mark A
MA
Russell
Barbara B
BB
Chen
Helen Y
HY
Chen
Chi-Dean
CD
Liang
Matthew W
MW
Mahoney
James W
JW
Malecha
Julie M
JM
Miyashiro
Stella S
SS
Yu
Leslie J
LJ
Askonas
James K
JK
Gierse
Elizabeth I
EI
Harding
Maureen K
MK
Highkin
James F
JF
Kachur
Suzanne H
SH
Kim
Doreen
D
Villani-Price
E Yvonne
EY
Pyla
Nayereh S
NS
Ghoreishi-Haack
Walter G
WG
Smith
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