Second-generation leukotriene B4 receptor antagonists related to SC-41930: heterocyclic replacement of the methyl ketone pharmacophore.
Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Extensive structure-activity relationship studies, in which a series of heterocyclic replacements for the methyl ketone functional group of SC-41930 was explored, identified SC-50605 (7-[3-[2-(cyclopropylmethyl)-3-methoxy-4- (4-thiazolyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- carboxylic acid) as an optimized analog within a series of thiazoles. SC-50605 was found to be significantly more potent than SC-41930 in LTB4 receptor binding, chemotaxis, and degranulation assays. It also displayed very good activity in animal models of colitis and epidermal inflammation by oral, topical, intravenous, and intracolonic routes of administration. The resolved enantiomers of SC-50605 were obtained by chiral chromatography and both demonstrated good in vitro and in vivo activity. The (+)-isomer (SC-52798) is currently being evaluated as a potential clinical candidate for psoriasis and ulcerative colitis therapy.
Penning
T D
TD
Department of Chemistry, Searle Research and Development, Skokie, Illinois 60077.
Djuric
S W
SW
Miyashiro
J M
JM
Yu
S
S
Snyder
J P
JP
Spangler
D
D
Anglin
C P
CP
Fretland
D J
DJ
Kachur
J F
JF
Keith
R H
RH
D000595:Amino Acid Sequence; D000818:Animals; D001393:Azoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D001393:Azoles; D001578:Benzopyrans; D002630:Chemotactic Factors; D018102:Receptors, Leukotriene B4; D013844:Thiazoles; C059950:SC 41930; C082207:SC 50605; D009240:N-Formylmethionine Leucyl-Phenylalanine