Synthesis and platelet aggregation inhibiting activity of acid side-chain modified hydantoin prostaglandin analogues.
A series of hydantoin prostaglandin analogues, in which the hexamethylene moiety of the acid side chain was replaced by other spacing groups possessing either ether, sulphide and/or olefin functionality, were prepared and evaluated for platelet aggregation inhibiting activity. The 4-thia analogue 13*) proved to be the most potent inhibitor (ca. 22x PGE1) and the 3-thia- and 3-oxa-analogues, 6 and 10 respectively, are approximately equipotent with BW245C (ca. 14x PGE1). Z-olefinic analogues (e.g. 11) were usually more potent than their E-isomers (e.g. 12). Structure-activity relationships are discussed in detail.
Barraclough
P
P
Department of Medicinal Chemistry, Wellcome Research Laboratories, Beckenham, Kent, U.K.
Caldwell
A G
AG
Glen
R C
RC
Harris
C J
CJ
Stepney
R
R
Whittaker
N
N
Whittle
B J
BJ
D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011453:Prostaglandins / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000959:Antihypertensive Agents; D006827:Hydantoins; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D000527:Alprostadil