(2-Piperidine)- and (2-pyrrolidine)ethanones and -ethanols as inhibitors of blood platelet aggregation.
(E)-4-[4-(Methylthio)phenyl]-1-(2-piperidinyl)-3-buten-2-one hydrochloride (44, RMI 14 133A) was found to inhibit ADP-induced aggregation of blood platelets. It was selected from a large series of (2-piperidinyl)- and (2-pyrrolidinyl)ethanones synthesized by a modified Schopf reaction from enolate magnesium salts of beta-keto acids and 2,3,4,5-tetrahydropyridine trimer or 3,4-dihydro-2H-pyrrole trimer, respectively. Evaluation of the compounds was carried out in vitro on human blood platelets. Structure-activity relationships are discussed. 44 also inhibited platelet aggregation ex vivo in guinea pigs. Subacute toxicity evaluation in dogs and guinea pigs showed it to have an unfavorable therapeutic ratio. 1-[4'-Chloro(1,1'-biphenyl)-4-yl-a1-2-(2-piperdinyl)ethanone hydrochloride (18, RMI 12436A) was found to lower serum cholesterol levles in rats with concurrent accumulation of (3beta)-cholesta-5,7-dien-3-ol, suggesting inhibition of 7-dehydrocholesterol delta7-reductase.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002775:Cholestadienols / Q000097:blood; D002784:Cholesterol / Q000097:blood; D003864:Depression, Chemical; D004285:Dogs; D000431:Ethanol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010977:Platelet Factor 3 / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D002775:Cholestadienols; D010880:Piperidines; D011759:Pyrrolidines; D010977:Platelet Factor 3; D000431:Ethanol; D000244:Adenosine Diphosphate; D002784:Cholesterol