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Optimization of ketone-based P2Y12 receptor antagonists as antithrombotic agents: Pharmacodynamics and receptor kinetics considerations
Institution:1. Medicinal Chemistry, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden;2. Bioscience, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden;3. DMPK AstraZeneca R&D, CVMD iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden;1. Department of Chemistry, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Department of In Vitro Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;3. Department of Pharmacology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;4. Department of Drug Metabolism, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;5. Department of Basic Pharmaceutical Sciences, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;6. Department of Oncology, Merck & Co., 33 Avenue Louis Pasteur, Boston, MA 02115, USA;1. Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA;2. Merck Research Laboratories West Point, 770 Sumneytown Pike, West Point, PA 19486, USA;1. Department of Medicinal Chemistry, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;2. Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;3. Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;1. Novartis Pharma AG, Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland;2. Novartis Institutes for BioMedical Research, Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan
Abstract:Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic–pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described.
Keywords:Acute coronary syndrome (ACS)  Acyl sulfonamides  Ketones  Esters  Piperidinyl-pyridines  Platelet aggregation  Receptor kinetics  Thromboembolism
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