Piperazinyl glutamate pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation.
J Med Chem
; 53(5): 2010-37, 2010 Mar 11.
Article
in En
| MEDLINE
| ID: mdl-20141147
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 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Piperazines
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Pyridines
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Platelet Aggregation Inhibitors
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Purinergic P2 Receptor Antagonists
Limits:
Adolescent
/
Adult
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Aged
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Animals
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Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2010
Document type:
Article
Affiliation country:
United States
Country of publication:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
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EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
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US
/
USA