Part II: Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 4, 2010, Pages 1388-1394

  Parlow, John J ^a   Burney, Mary W ^a   Case, Brenda L ^a   Girard, Thomas J ^a   Hall, Kerri A ^a   Harris, Peter K ^a   Hiebsch, Ronald R ^a   Huff, Rita M ^a   Lachance, Rhonda M ^a   Mischke, Deborah A ^a   Rapp, Stephen R ^a   Woerndle, Rhonda S ^a   Ennis, Michael D ^a  

^a PFIZER INC   (United States)

Author keywords

Antiplatelet; Antithrombotic; Cardiovascular disease; GPCR antagonist; P2Y12 receptor

Indexed keywords

PIPERAZINYL GLUTAMATE PYRIDINE; PIPERIDINE DERIVATIVE; PURINERGIC P2Y12 RECEPTOR; UNCLASSIFIED DRUG;

ARTICLE; DRUG BINDING; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; NONHUMAN; STRUCTURE ACTIVITY RELATION; THROMBOCYTE AGGREGATION INHIBITION;

ADMINISTRATION, ORAL; ANIMALS; CHO CELLS; CRICETINAE; CRICETULUS; DOGS; FIBRINOLYTIC AGENTS; GLUTAMIC ACID; HUMANS; INHIBITORY CONCENTRATION 50; MOLECULAR STRUCTURE; PIPERIDINES; PLATELET AGGREGATION; PYRIDINES; RATS; RECEPTORS, PURINERGIC P2; STRUCTURE-ACTIVITY RELATIONSHIP;

CANIS FAMILIARIS; RATTUS;

EID: 75449085190     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.12.110     Document Type: Article

References (12)

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8. 50 value of the functional assay was attributed to protein binding.
9. The Pfizer Institutional Animal Care and Use Committee reviewed and approved the animal use in these studies. The animal care and use program is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International.
10. Compound 4t solubility: 921 μM at pH 2.0; 195 μM at pH 6.5; 969 μM at pH 9.0. Compound 5t solubility: 299 μM at pH 2.0; 48 μM at pH 6.5; 1291 μM at pH 9.0.
11. 50's in the PRP assay.
12. Definitive human PPB data: 4t Fu 3.4% at 0.2 μM, 4.4% at 2 μM, and 3.3% at 10 μM; 5t Fu 5.3% at 0.2 μM, 5.7% at 2 μM, and 6.1% at 10 μM. Neither showed concentration-dependent PPB.