Development of orally active nonpeptidic inhibitors of human neutrophil elastase.
5-Amino-2-phenylpyrimidin-6-ones, some of their desamino derivatives, and miscellaneous derivatives were synthesized and biologically evaluated on both in vitro activity and oral activity in an acute hemorrhagic assay. These compounds contained an alpha-keto-1,3,4-oxadiazole moiety to bind covalently to the Ser-195 hydroxy group of human neutrophil elastase (HNE). Among those tested, compounds 11a-c,e,i-l(F), 11d,e,k(H), 21d,e,k(F), and 21d,e(H) showed a good oral profile. RS-Mixture 3(H) was selected for clinical evaluation based on its oral potency, duration of action, enzyme selectivity, safety profile, and ease of synthesis. Structure-activity relationships (SARs) are discussed.
Ohmoto
K
K
Cortech, Inc., 6850 North Broadway, Denver, Colorado 80221, USA.
Yamamoto
T
T
Okuma
M
M
Horiuchi
T
T
Imanishi
H
H
Odagaki
Y
Y
Kawabata
K
K
Sekioka
T
T
Hirota
Y
Y
Matsuoka
S
S
Nakai
H
H
Toda
M
M
Cheronis
J C
JC
Spruce
L W
LW
Gyorkos
A
A
Wieczorek
M
M
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D006868:Hydrolysis; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008171:Lung Diseases / Q000188:drug therapy; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D019272:Leukocyte Elastase