Synthesis and activity of N-cyanoguanidine-piperazine P2X7 antagonists.
A novel series of cyanoguanidine-piperazine P2X(7) antagonists were identified and structure-activity relationship (SAR) studies described. Compounds were assayed for activity at human and rat P2X(7) receptors in addition to their ability to inhibit IL-1 beta release from stimulated human whole blood cultures. Compound 27 possesses potent activity (0.12 microM) in this latter assay and demonstrates moderate clearance in-vivo.
Betschmann
Patrick
P
Abbott Bioresearch Center, Department of Medicinal Chemistry, 381 Plantation Street, Worcester, MA 01605, USA.
Bettencourt
Brian
B
Donnelly-Roberts
Diana
D
Friedman
Michael
M
George
Jonathan
J
Hirst
Gavin
G
Josephsohn
Nathan
N
Konopacki
Donald
D
Li
Biqin
B
Maull
John
J
Morytko
Michael J
MJ
Moore
Nigel Stjohn
NS
Namovic
Marian
M
Rafferty
Paul
P
Salmeron-Garcia
Jose-Andres
JA
Tarcsa
Edit
E
Wang
Lu
L
Woller
Kevin
K
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006146:Guanidines / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D008956:Models, Chemical; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000737:chemistry; D058486:Receptors, Purinergic P2X7; D013329:Structure-Activity Relationship
D006146:Guanidines; D053583:Interleukin-1beta; C546468:P2RX7 protein, human; C546470:P2rx7 protein, rat; D010879:Piperazines; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000077489:Piperazine; C004711:dicyandiamido