New potent antagonists of leukotrienes C4 and D4. 1. Synthesis and structure-activity relationships.
(p-Amylcinnamoyl)anthranilic acid (3a) had moderate antagonist activities against LTD4-induced smooth muscle contraction on guinea pig ileum and LTC4-induced bronchoconstriction in anesthetized guinea pigs. Modifications were made in the hydrophobic part (cinnamoyl moiety) and the hydrophilic part (anthranilate moiety) of 3a. A series of 8-(benzoylamino)-2-tetrazol-5-yl-1,4-benzodioxans and 8-(benzoylamino)-2-tetrazol-5-yl-4-oxo-4H-1-benzopyrans were revealed to be potent antagonists of leukotrienes C4 and D4. Among both series, ONO-RS-347 (18k) and ONO-RS-411 (19h) were the most potent and orally active antagonists, respectively. Structure-activity relationships are discussed.
Nakai
H
H
Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Konno
M
M
Kosuge
S
S
Sakuyama
S
S
Toda
M
M
Arai
Y
Y
Obata
T
T
Katsube
N
N
Miyamoto
T
T
Okegawa
T
T
D000818:Animals; D001993:Bronchodilator Agents / Q000138:chemical synthesis*; D002934:Cinnamates / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009119:Muscle Contraction / Q000187:drug effects*; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology
D001993:Bronchodilator Agents; D002934:Cinnamates; D013189:SRS-A; D062367:ortho-Aminobenzoates