Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids as leukotriene biosynthesis inhibitors.
A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure-activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB(4) biosynthesis in the intact human neutrophil with IC(50) of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED(50) = 0.14 mg/kg) and rat anaphylaxis model (ED(50) = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE(4) biosynthesis (ED(50) of 0.1 mg/kg) and eosinophil influx (ED(50) of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.
Kolasa
T
T
Immunoscience Research, Abbott Laboratories, D47K, AP10, 100 Abbott Park Road, Abbott Park, Illinois 600064, USA. teodozyj.kolasa@abbott.com
Gunn
D E
DE
Bhatia
P
P
Woods
K W
KW
Gane
T
T
Stewart
A O
AO
Bouska
J B
JB
Harris
R R
RR
Hulkower
K I
KI
Malo
P E
PE
Bell
R L
RL
Carter
G W
GW
Brooks
C D
CD
D000180:Acrylic Resins; D000707:Anaphylaxis / Q000188:drug therapy; D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001202:Ascitic Fluid / Q000378:metabolism; D006099:Granuloma / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011001:Pleuropneumonia / Q000188:drug therapy; D011014:Pneumonia / Q000188:drug therapy; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099166:Polyacrylamides
D000180:Acrylic Resins; D018926:Anti-Allergic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007975:Leukotriene B4; D011804:Quinolines; D000099166:Polyacrylamides; C112380:A 93176