Synthesis and inhibitory activity on platelet aggregation of 13'-aza and other omega-chain modified BW245C analogues.
BW245C analogues which have 15'-keto, -oximino, -sulphinyl, -sulphonyl, -methyl, -1-adamantyl, 14'-hydroxy, 16'-hydroxy, 13'-14'-NH=CH, -NH-CH2, or -NH-CO groups have been synthesized and evaluated for their activity in inhibiting platelet aggregation and for their cardiovascular actions: the 13'-aza analogues 13 and 14 are more potent inhibitors of human platelet aggregation than BW245C (0.3, 0.6 and 0.2 x PGI2, respectively) and these inhibitory activities on platelet aggregation increase on incubation in vitro. The prostaglandin mimetic properties of 13 (BW68C) and 14 (BW361C) were studied in more detail and their platelet inhibitory and vasodilatory effects found to be of longer duration than those of BW245C. All other modifications to the omega-chain of BW245C led to less potent or inactive compounds.
Barraclough
P
P
Department of Medicinal Chemistry, Wellcome Research Laboratories, Beckenham, Kent, U.K.
Brockwell
M
M
Caldwell
A G
AG
Demaine
D A
DA
Harris
C J
CJ
King
W R
WR
Stepney
R J
RJ
Wharton
C J
CJ
Whittle
B J
BJ
D000818:Animals; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
D006827:Hydantoins; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; C087760:3-((2-cyclohexyl-2-hydroxyethylidene)amino)-2,5-dioxo-4-imidazolidineheptanoic acid; C030669:BW 245C