Part II: piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation.
Efforts to refine the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog.
Parlow
John J
JJ
Department of Medicinal Chemistry, Pfizer Global Research & 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
Harris
Peter K
PK
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
D000284:Administration, Oral; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D058925:Receptors, Purinergic P2Y12; D013329:Structure-Activity Relationship
D005343:Fibrinolytic Agents; C548576:P2RY12 protein, human; C553058:P2ry12 protein, rat; D010880:Piperidines; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines; D058925:Receptors, Purinergic P2Y12; D018698:Glutamic Acid