From ATP to AZD6140: the discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis.
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
Springthorpe
Brian
B
AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK. brian.springthorpe@astrazeneca.com
Bailey
Andrew
A
Barton
Patrick
P
Birkinshaw
Timothy N
TN
Bonnert
Roger V
RV
Brown
Roger C
RC
Chapman
David
D
Dixon
John
J
Guile
Simon D
SD
Humphries
Robert G
RG
Hunt
Simon F
SF
Ince
Francis
F
Ingall
Anthony H
AH
Kirk
Ian P
IP
Leeson
Paul D
PD
Leff
Paul
P
Lewis
Richard J
RJ
Martin
Barrie P
BP
McGinnity
Dermot F
DF
Mortimore
Michael P
MP
Paine
Stuart W
SW
Pairaudeau
Garry
G
Patel
Anil
A
Rigby
Aaron J
AJ
Riley
Robert J
RJ
Teobald
Barry J
BJ
Tomlinson
Wendy
W
Webborn
Peter J H
PJ
Willis
Paul A
PA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000255:Adenosine Triphosphate / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D058919:Purinergic P2 Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013927:Thrombosis / Q000517:prevention & control*; D000077486:Ticagrelor