The design and synthesis of second generation leukotriene B4 (LTB4) receptor antagonists related to SC-41930.
SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB4 receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7-16 times more potent than SC-41930 in LTB4 receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB4-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically.
Penning
T D
TD
Department of Chemistry, Searle Research and Development, Skokie, IL 60077.
Djuric
S W
SW
Docter
S H
SH
Yu
S S
SS
Spangler
D
D
Anglin
C P
CP
Fretland
D J
DJ
Kachur
J F
JF
Keith
R H
RH
Tsai
B S
BS
D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D015550:Cell Degranulation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy*; D003872:Dermatitis / Q000188:drug therapy*; D004195:Disease Models, Animal; D015195:Drug Design; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D051379:Mice; D018102:Receptors, Leukotriene B4 / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
D001578:Benzopyrans; D018102:Receptors, Leukotriene B4; D013844:Thiazoles; C059950:SC 41930; C082207:SC 50605; D007975:Leukotriene B4