P2Y1 receptor antagonists as novel antithrombotic agents

• Published in: Bioorganic & medicinal chemistry letters Vol. 18; no. 11; pp. 3338 - 3343
• Main Authors: PFEFFERKORN, Jeffrey A, CHOI, Chulho, LEININGER, Michael T, GEYER, Andrew, SCHEFZICK, Sabine, ATHERTON, James, WINTERS, Thomas, KENNEDY, Robert, LIGUO CHI, PERRIN, Lisa A, LU, Gina, PING, Yun-Wen, MCCLANAHAN, Tom, SCHROEDER, Richard
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01.06.2008
• Subjects: Adenosine Diphosphate - pharmacology; Administration, Oral; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Combinatorial Chemistry Techniques; Drug Design; Fibrinolytic Agents - chemical synthesis; Fibrinolytic Agents - chemistry; Fibrinolytic Agents - pharmacology; Humans; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2Y1; Structure-Activity Relationship; Intravenous administration; Rat; Cardiovascular disease; Anticoagulant; P2Y1 receptor; P2Y1 purinergic receptor; Structure activity relation; G protein coupled receptor; Chlorine Organic compounds; Antithrombotic agent; Pyrazole derivatives; Ureas; Antagonist; Chemical synthesis; GPCR antagonist; Rodentia; Oral administration; In vitro; Antiplatelet agent; In vivo; Vertebrata; Antiplatelet; Mammalia; Animal; Antithrombotic; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2008.04.028

The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable.