New carbamoylpiperidines as human platelet aggregation inhibitors

A series of 3-carbamoylpiperidines (nipecotamides) are designed, synthesized and tested for their inhibitory action against adenosine diphosphate (ADP)-induced aggregation of human platelets. A structure-activity analysis of the bis(nipecotamido)aralkane type showed that a substituent on the piperid...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2000-05, Vol.8 (5), p.1041-1058
Main Authors: ZHENGMING GUO, XIAOZHANG ZHENG, THOMPSON, W, DUGDALE, M, GOLLAMUDI, R
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Female
Humans
Inositol 1,4,5-Trisphosphate - metabolism
Magnetic Resonance Spectroscopy
Male
Medical sciences
Pharmacology. Drug treatments
Piperidines - chemistry
Piperidines - pharmacology
Platelet Aggregation Inhibitors - chemistry
Platelet Aggregation Inhibitors - pharmacology
Spectrophotometry, Infrared
Structure-Activity Relationship
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Summary:A series of 3-carbamoylpiperidines (nipecotamides) are designed, synthesized and tested for their inhibitory action against adenosine diphosphate (ADP)-induced aggregation of human platelets. A structure-activity analysis of the bis(nipecotamido)aralkane type showed that a substituent on the piperidine ring should preferably be an amide and that the electronegativity of the carbonyl oxygen and the orientation of the amide group affected activities. Based on the knowledge of factors influencing platelet activation and aggregation, a nitric ester moiety which could release nitric oxide (NO) in situ, is incorporated into the nipecotamide structure. These compounds exhibit increased activity compared to those having no -ONO2 function. They also show stereoselectivity, with the meso isomer being approximately twice as potent as the synthetic diastereomeric mixture. Replacement of the -ONO2 function with hydroxyl, ester or alkyl groups considerably diminishes aggregation-inhibitory potential. Nipecotamides are shown here to inhibit the basal and collagen-induced rise in platelet inositol trisphosphate (IP3) levels, as well as phosphoinositide turnover. A comprehensive mechanism of action is proposed taking earlier results into consideration.
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(00)00033-X