- Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy
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In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.
- Miller, Michael M.,Banville, Jacques,Friends, Todd J.,Gagnon, Mark,Hangeland, Jon J.,Lavallée, Jean-Fran?ois,Martel, Alain,O'Grady, Harold,Rémillard, Roger,Ruediger, Edward,Tremblay, Fran?ois,Posy, Shana L.,Allegretto, Nick J.,Guarino, Victor R.,Harden, David G.,Harper, Timothy W.,Hartl, Karen,Josephs, Jonathan,Malmstrom, Sarah,Watson, Carol,Yang, Yanou,Zhang, Ge,Wong, Pancras,Yang, Jing,Bouvier, Michel,Seiffert, Dietmar A.,Wexler, Ruth R.,Lawrence, R. Michael,Priestley, E. Scott,Marinier, Anne
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p. 7400 - 7416
(2019/08/26)
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- HETEROBICYCLICALLY SUBSTITUTED 4-OXOBUTANE ACID DERIVATIVES AND USE THEREOF
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The present application relates to novel heterobicyclically substituted 4-oxobutanoic acid derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases and to their use for producing medicaments for the treatment and/or prevention of diseases, especially for the treatment and/or prevention of respiratory, pulmonary and cardiovascular disorders.
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Paragraph 0474-0477
(2017/05/19)
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- NEW ARYLALKENYLPROPARGYLAMINE DERIVATIVES EXHIBITING NEUROPROTECTIVE ACTION FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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The invention relates to novel arylalkenylpropargylamine derivatives of general formula (I) or enantiomers or diastereomers thereof or salts, optionally pharmaceutically acceptable salts, or solvates of any of these. The compounds can be used in treating or preventing a disease or condition in a mammal related to monoamine oxidase dysfunction, especially in neurodegenerative diseases, e.g. Parkinson's disease, Alzheimer's disease or Huntington's disease.
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Page/Page column 27; 41
(2015/06/25)
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