Structure-activity relationships study of two series of leukotriene B4 antagonists: novel indolyl and naphthyl compounds substituted with a 2-[methyl(2-phenethyl)amino]-2-oxoethyl side chain.
N-Methyl-N-phenethylphenylacetamide has been reported to be a key binding domain to LTB4 receptors. Here we describe the synthesis and structure-activity relationship (SAR) studies of two new series of LTB4 receptor antagonists in which the phenyl ring of this receptor binding domain is replaced with indole and naphthalene, respectively. Results of these studies indicate that, in addition to the 2-[methyl(2-phenethyl)amino]-2-oxoethyl moiety, the presence of an acid group and a lipophilic side chain, as well as the spatial relationship of these three functions, is crucial for high binding affinity with LTB4 receptors. Our SAR studies also reveal that an arenecarboxylic acid, or an enoic acid in which the carboxyl group is conjugated with the central ring, is the preferred polar group. The lipophilic side chain of the naphthyl series was found to tolerate minor variations, ranging from a phenylmethoxy group to phenyl and alkyloxy groups. The most active compounds are 2-ethyl-3-[1-[2-[methyl(2-phenethyl) amino]-2-oxoethyl]-5-(phenylmethoxy)indol-3-yl]propenoic+ ++ acid (4g) of the indolyl series and 4-[2-[methyl(2-phenethyl)amino]-2-oxoethyl]-8-(phenylmethoxy )-2-naphthalenecarboxylic acid (2a) or the naphthyl series, with IC50 of 8 and 4.7 nM respectively, in the receptor binding assay using intact human neutrophils.
Chan
W K
WK
Department of Medicinal Chemistry, Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426, USA.
Huang
F C
FC
Morrissette
M M
MM
Warus
J D
JD
Moriarty
K J
KJ
Galemmo
R A
RA
Dankulich
W D
WD
Poli
G
G
Sutherland
C A
CA
D000179:Acrylates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship
C101611:2-ethyl-3-(1-(2-(methyl(2-phenethyl)amino)-2-oxoethyl)-5-(phenylmethoxy)indol-3-yl)propenoic acid; D000179:Acrylates; D007211:Indoles; D009284:Naphthols; D010627:Phenethylamines; D018102:Receptors, Leukotriene B4; C077720:RG 14893; D007975:Leukotriene B4