title: Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation.
abstract: Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability.
authors: Department of Medicinal Chemistry, Pfizer Global Research & Development, Chesterfield, MO 63017, USA. john.j.parlow@pfizer.com
authors: John J
authors: JJ
authors: Parlow
authors: Mary W
authors: MW
authors: Burney
authors: Brenda L
authors: BL
authors: Case
authors: Thomas J
authors: TJ
authors: Girard
authors: Kerri A
authors: KA
authors: Hall
authors: Ronald R
authors: RR
authors: Hiebsch
authors: Rita M
authors: RM
authors: Huff
authors: Rhonda M
authors: RM
authors: Lachance
authors: Deborah A
authors: DA
authors: Mischke
authors: Stephen R
authors: SR
authors: Rapp
authors: Rhonda S
authors: RS
authors: Woerndle
authors: Michael D
authors: MD
authors: Ennis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018698:Glutamic Acid / Q000737:chemistry*; D006801:Humans; D008297:Male; D010879:Piperazines / Q000737:chemistry*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C548576:P2RY12 protein, human; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D011994:Recombinant Proteins; D018698:Glutamic Acid