Piperazinyl glutamate pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation.
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 through modifications at the 4-position of the pyridine ring and the terminal nitrogen of the piperazine ring, 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 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavailability. Compound 47s was selected for further preclinical evaluations.
Department of Medicinal Chemistry, Pfizer Global Research & Development, 700 Chesterfield Parkway West, Chesterfield, Missouri 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
Peter K
PK
Harris
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
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005971:Glutamates / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010879:Piperazines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D013329:Structure-Activity Relationship; D055815:Young Adult
D005971:Glutamates; 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