Platelet aggregation inhibitory activity and vasodepressor activity of a series of bicyclo[3.2.0]hept-6-ylidene iminoxy alkanoic acids with modified lower side chains.
Prostacyclin analogues derived from modification of the lower side chain of the bicyclo[3.2.0]hept-6-ylidene iminoxyacetic acid (1) were studied in inhibition of in vitro and ex vivo platelet aggregation and in the spontaneously hypertensive rat. Iminoxyacetic acids (13a), (13b), (13c) and iminoxypropionic acid (14b) were 2.9, 3.0, 1.9 and 2.0 times respectively more potent than PGE1 in inhibiting ADP-induced aggregation of human platelets in vitro. Following intravenous administration at a dose of 90-110 micrograms/kg in the guinea pig, iminoxyacetic acids (13a), (13c) and iminoxypropionic acid (14b) showed a maximum inhibition of 82-92% with a half life in the range of 14-22 min. Following oral administration at a dose of 1 mg/kg in the guinea pig, iminoxyacetic acids (13a) and (13b) inhibited heterologous platelet aggregation for 4.5 h. Following intravenous administration in spontaneously hypertensive rats, acids (13a)-(13c) and (14b) lowered the mean blood pressure in a dose dependent manner. At a dose of 100 micrograms/kg, the effect lasted for 20-40 min.
Institute of Organic Chemistry, Syntex Research, Palo Alto, California 94304.
C
C
O-Yang
H Y
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Wu
D J
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Kertesz
A F
AF
Kluge
M B
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Wallach
A L
AL
Willis
D L
DL
Smith
L F
LF
Chang
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D010975:Platelet Aggregation Inhibitors; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D002264:Carboxylic Acids; D010975:Platelet Aggregation Inhibitors