Synthesis of structural analogs of leukotriene B4 and their receptor binding activity.
Structural analogs of leukotriene B4 (LTB4) were designed using a preferred conformation of LTB4 (1). Appending an aromatic ring scaffold between LTB4 carbons 7 and 11 led to quinoline analogs 3 and 15. A similar modification to the LTB4 structure between carbons 7 and 9 led to the pyridine analogs 41 and 46. The compounds of this study were evaluated in receptor binding assays using [3H]LTB4 and intact human DMSO differentiated U-937 cells. The first analog prepared, quinoline 3, displayed moderate potency in the LTB4 receptor binding assay (Ki = 0.9 microM). Modification of 3 by appending an aromatic ring between carbons 2 and 4 of the acid side chain produced a dramatic increase in receptor binding (15, Ki = 0.01 microM); a further improvement in receptor binding was achieved in the pyridine series (e.g., 41; Ki = 0.001 microM). The LTB4 receptor agonist/antagonist activity of the test compounds was determined using a functional assay that relies upon intracellular calcium mobilization induced by LTB4. Of the analogs prepared in this report only 47 demonstrated LTB4 receptor antagonist activity.
Kingsbury
W D
WD
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Pendrak
I
I
Leber
J D
JD
Boehm
J C
JC
Mallet
B
B
Sarau
H M
HM
Foley
J J
JJ
Schmidt
D B
DB
Daines
R A
RA
D006801:Humans; D007975:Leukotriene B4 / Q000031:analogs & derivatives* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011725:Pyridines; D011804:Quinolines; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4