title: Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y(12) antagonists for inhibition of platelet aggregation.
abstract: 2-Phenyl-pyrimidine-4-carboxamide analogs were identified as P2Y12 antagonists. Optimization of the carbon-linked or nitrogen-linked substituent at the 6-position of the pyrimidine ring provided compounds with excellent ex vivo potency in the platelet aggregation assay in human plasma. Compound 23u met the objectives for activity, selectivity and ADMET properties.
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. Electronic address: eva.caroff@actelion.com.
authors.forename: Eva
authors.initials: E
authors.lastname: Caroff
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hilpert
authors.affiliation: Actelion Pharmaceuticals Ltd, Drug Discovery and Preclinical Research & Development, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Riederer
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D005971:Glutamates; D058921:Purinergic P2Y Receptor Antagonists; D011743:Pyrimidines
keywords: Antiplatelet; Antithrombotic; GPCR antagonist; P2Y(12) antagonist; P2Y(12) receptor