Studies on antiallergic agents. I. Synthesis and antiallergic activity of novel pyrazine derivatives.
Various pyrazine derivatives were synthesized and their antiallergic activity was examined. The inhibitory activity on allergic histamine release of the compounds bearing a 5-tetrazolyl group was more potent than that of the corresponding carboxyl derivatives. The introduction of -CONH- or -NHCO- between the pyrazine ring and the 5-tetrazolyl group as a spacer greatly enhanced the activity. N-(1H-Tetrazol-5-yl)-2-pyrazinecarboxamide (I-3) was estimated to exhibit nearly the same potency as disodium cromoglycate (DSCG). The structure-activity relationship among various derivatives modified by introducing some substituents onto the 3-, 5- or 6-position of the pyrazine ring of I-3 was investigated. The activity remained unchanged or was reduced when such substituents as methyl, chloro, methoxy, methylamino and dimethylamino were introduced at the 3- or 5-position. In contrast, 6-substitution with various alkylamino groups more or less increased the activity. Among them, the 6-dimethylamino (I-17c) and 6-(1-pyrrolidinyl) (I-34) derivative were proved to be most potent. The IC50 values (concentration which produces 50% inhibition of the allergic histamine release) of I-17c and I-34 were determined to be 4.7 x 10(-10) and 4.6 x 10(-10) M, respectively. These two compounds produced a potent inhibitory activity on passive cutaneous anaphylaxis (PCA) in rat, not only by the intravenous route (ED50 = 0.0096 mg/kg for both compounds) but also by the oral route (ED50 = 0.19 and 0.18 mg/kg, respectively). On the other hand, when the pyrazine ring of some representative compounds was replaced with a pyridine ring, the inhibitory activity on histamine release was significantly reduced.
Central Research Laboratories, Hokuriku Seiyaku Co., Ltd., Fukui, Japan.
E
E
Makino
N
N
Iwasaki
N
N
Yagi
T
T
Ohashi
H
H
Kato
Y
Y
Ito
H
H
Azuma
D000818:Animals; D001200:Ascaris / Q000276:immunology; D006633:Histamine Antagonists / Q000138:chemical synthesis*; D006636:Histamine Release / Q000187:drug effects*; D008297:Male; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D006633:Histamine Antagonists; D011719:Pyrazines