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.
Parlow
John J
JJ
Department of Medicinal Chemistry, Pfizer Global Research and Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. john.j.parlow@pfizer.com
Burney
Mary W
MW
Case
Brenda L
BL
Girard
Thomas J
TJ
Hall
Kerri A
KA
Hiebsch
Ronald R
RR
Huff
Rita M
RM
Lachance
Rhonda M
RM
Mischke
Deborah A
DA
Rapp
Stephen R
SR
Woerndle
Rhonda S
RS
Ennis
Michael D
MD
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