Optimization of ketone-based P2Y(12) receptor antagonists as antithrombotic agents: pharmacodynamics and receptor kinetics considerations.
Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic-pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described.
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. Electronic address: fgiordanetto@tarosdiscovery.com.
Fabrizio
F
Giordanetto
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Peter
P
Bach
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Fredrik
F
Zetterberg
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Thomas
T
Antonsson
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Ruth
R
Bylund
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Johan
J
Johansson
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Mikael
M
Sellén
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
David
D
Brown
Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Lotta
L
Hideståhl
Bioscience, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Pia
P
Berntsson
DMPK AstraZeneca R&D, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Daniel
D
Hovdal
Bioscience, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Helen
H
Zachrisson
Bioscience, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Jan-Arne
JA
Björkman
Bioscience, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
J J J
JJ
van Giezen
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D016466:CHO Cells; D018938:Caco-2 Cells; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D005343:Fibrinolytic Agents; D007659:Ketones; D010975:Platelet Aggregation Inhibitors; D058925:Receptors, Purinergic P2Y12
Acute coronary syndrome (ACS); Acyl sulfonamides; Esters; Ketones; P2Y(12) receptor; Piperidinyl-pyridines; Platelet aggregation; Receptor kinetics; Thromboembolism