Piperazinyl-glutamate-pyrimidines as potent P2Y12 antagonists for inhibition of platelet aggregation.
Piperazinyl-glutamate-pyrimidines were prepared with oxygen, nitrogen, and sulfur substitution at the 4-position of the pyrimidine leading to highly potent P2Y12 antagonists. In particular, 4-substituted piperidine-4-pyrimidines provided compounds with exceptional potency. Pharmacokinetic and physicochemical properties were fine-tuned through modifications at the 4-position of the piperidine ring leading to compounds with good human PRP potency, selectivity, clearance and oral bioavailability.
Department of Medicinal Chemistry, Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. john.j.parlow@pfizer.com
John J
JJ
Parlow
Mary W
MW
Burney
Brenda L
BL
Case
Thomas J
TJ
Girard
Kerri A
KA
Hall
Ronald R
RR
Hiebsch
Rita M
RM
Huff
Rhonda M
RM
Lachance
Deborah A
DA
Mischke
Stephen R
SR
Rapp
Rhonda S
RS
Woerndle
Michael D
MD
Ennis
D000818:Animals; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018698:Glutamic Acid / Q000737:chemistry*; D006801:Humans; D008297:Male; D010880:Piperidines / Q000737:chemistry*; D010974:Platelet Aggregation / Q000187:drug effects*; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D013329:Structure-Activity Relationship
D005343:Fibrinolytic Agents; C548576:P2RY12 protein, human; D010880:Piperidines; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D018698:Glutamic Acid; C032727:piperidine