- 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
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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.
- Caroff, Eva,Hubler, Francis,Meyer, Emmanuel,Renneberg, Dorte,Gnerre, Carmela,Treiber, Alexander,Rey, Markus,Hess, Patrick,Steiner, Beat,Hilpert, Kurt,Riederer, Markus A.
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p. 9133 - 9153
(2015/12/23)
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- Light-mediated deoxygenation of alcohols with a dimeric gold catalyst
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A new protocol for the reductive deoxygenation of primary alcohols was explored. This photo-mediated method combines a novel approach to bromination of alcohols merged with the powerful reducing capability of [Au2(dppm)2]Cl2 [dppm = 1,1-bis(diphenylphosphino)methane] as a photoredox catalyst. The highly efficient methods discussed are marked by the use of UVA light-emitting diodes, which have significantly reduced reaction times and lowered setup cost.
- McCallum, Terry,Slavko, Ekaterina,Morin, Mathieu,Barriault, Louis
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supporting information
p. 81 - 85
(2015/02/18)
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- Concise Synthesis of Enantiomerically Pure (1′S,2′R)-and (1′R,2′S)-2S-Amino-3-(2′-aminomethyl-cyclopropyl)propionic Acid: Two E-Diastereoisomers of 4,5-Methano-l-lysine
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A concise synthesis of both E-isomers of 2S-amino-3-(2′-aminomethyl- cyclopropyl)propionic acid, new methano-l-lysines, is described. The synthetic route includes nine steps from l-methionine, with a key step involving the cyclopropanation of an intermediate E-allylic alcohol. The resultant hydroxymethylcyclopropanes were readily separated and converted into the title α-amino acids. The stereochemistry around the cyclopropane rings was deduced by conducting the cyclopropanation in the presence of N,N,N′,N′-tetramethyl-d-tartaric acid diamide butylboronate, a chiral controller which is known to favour the production of S-hydroxymethyl cyclopropanes from allylic alcohols.
- Altamore, Timothy M.,Nguyen, Oanh T. K.,Churches, Quentin I.,Cavanagh, Kate,Nguyen, Xuan T. T.,Duggan, Sandhya A. M.,Krippner, Guy Y.,Duggan, Peter J.
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p. 1105 - 1111
(2013/09/24)
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- PHOSPHONIC ACID DERIVATES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
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The invention relates to 2-phenyl-pyrimidine derivatives containing a phosphonic acid motif and their use as P2Y12 receptor antagonists in the treatment and/or prevention 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. (I).
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Page/Page column 68
(2009/07/03)
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