Designing prostacyclin analogues.
A series of prostacyclin analogues were synthesized and investigated for influence on blood pressure in rats, in vivo inhibition of platelet aggregation in rats, and in vitro inhibition of platelet aggregation in human platelet-rich plasma. The common feature of the analogues described is a replacement of C1-C4 of prostacyclin by a carboxyphenylene residue. The following structure-activity relationships were obtained. Only the meta-carboxyphenylene derivatives yield substantial prostacyclin activity. The 2,3,4-trinor-1,5-inter-m-phenylene prostacyclin analogues in contrast to the natural prototype are reasonably stable against hydrolysis of the enolether bond. The corresponding 2,3,4-trinor-1,5-inter-m-phenylene analogues of carbaprostacyclin have a somewhat lower specific activity but are superior in stability at acid pH values. With regard to the stereoisomerism at the delta 5 double bond, the Z-isomers of the oxa-cyclic prostacyclin series and the E-isomers of the carba-cyclic prostacyclin series are substantially more active than their counterparts. As with natural prostacyclin, the OH group at C15 has to be present in S-configuration. The "wrong" isomers do not inhibit prostacyclin-dependent effects. Resistance against 15-hydroxyprostaglandin dehydrogenase is achieved by substitutions at or near C15. Optimum specific activity combined with resistance against all known prostaglandin-activating enzymes is observed in prostacyclin and carbaprostacyclin analogues, in which the terminal n-pentyl residue is replaced by cyclohexyl. Duration of action, i.e. lowering of blood pressure in anaesthesized rats and inhibition of platelet aggregation in anaesthesized rats, was investigated with selected analogues in order to check the consequences of chemical and metabolic stabilization.(ABSTRACT TRUNCATED AT 250 WORDS)
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors; D000758:Anesthesia; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D000242:Cyclic AMP / Q000097:blood; D004355:Drug Stability; D011464:Epoprostenol / Q000138:chemical synthesis*; D006736:Horses; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects; D011465:Prostaglandins, Synthetic / Q000138:chemical synthesis*; D051381:Rats
D001095:Arachidonic Acids; D011465:Prostaglandins, Synthetic; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D000242:Cyclic AMP; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase