325685-59-4Relevant articles and documents
4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y12 Receptor Antagonist with a Wider Therapeutic Window in the Rat Than Clopidogrel
Caroff, Eva,Hubler, Francis,Meyer, Emmanuel,Renneberg, Dorte,Gnerre, Carmela,Treiber, Alexander,Rey, Markus,Hess, Patrick,Steiner, Beat,Hilpert, Kurt,Riederer, Markus A.
, p. 9133 - 9153 (2015/12/23)
Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.
Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y12 antagonists for inhibition of platelet aggregation
Caroff, Eva,Meyer, Emmanuel,Treiber, Alexander,Hilpert, Kurt,Riederer, Markus A.
, p. 4323 - 4331 (2014/10/15)
2-Phenyl-pyrimidine-4-carboxamide analogs were identified as P2Y 12 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
2-PHENYL-6-AMINOCARBONYL-PYRIMIDINE DERIVATIVES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
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Page/Page column 20, (2010/01/29)
The invention relates to 2-phenyl-6-aminocarbonyl-pyrimidine derivatives and their use as P2Y12 receptor antagonists in the treatment and/or prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. Formula (I).
2-PHENYL-6-AMINOCARBONYL-PYRIMIDINE DERIVATIVES AND THEIR USE AS P2Y12 RECEPTOR
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Page/Page column 12, (2009/12/05)
The invention relates to 2-phenyl-6-aminbcarbonyl-pyrimidinc derivatives and their use as P2Y12 receptor antagonists in the treatment and/or prevention and/or treatment of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. Formula (1).
Enforced helicity: Efficient access to self-organized helical molecular strands by the imine route
Gardinier, Kevin M.,Khoury, Richard G.,Lehn, Jean-Marie
, p. 4124 - 4131 (2007/10/03)
The condensation of the two oligoheterocyclic aldehydes 8 and 16 with the bis-hydrazine 17 gives the bis-hydrazones 1 and 2. These molecular strands are shown to adopt helical conformations of 1.5 and 2.5 turns, respectively. The helical shape of 1 has be
