title: Part II: piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Global Research & Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA. john.j.parlow@pfizer.com
authors.forename: John J
authors.initials: JJ
authors.lastname: Parlow
authors.forename: Mary W
authors.initials: MW
authors.lastname: Burney
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Case
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Girard
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Hall
authors.forename: Peter K
authors.initials: PK
authors.lastname: Harris
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Hiebsch
authors.forename: Rita M
authors.initials: RM
authors.lastname: Huff
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Lachance
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Mischke
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Rapp
authors.forename: Rhonda S
authors.initials: RS
authors.lastname: Woerndle
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ennis
mesh_terms: 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
chemical_list: 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