- 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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- SUBSTITUTED 2-PHENYL-PYRIDINE DERIVATIVES
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The present invention relates to compounds of formula I wherein R1, R2, R4, R5, Ra, Rb, n, W and Z are as defined in the application, their preparation 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.
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Page/Page column 32
(2011/04/14)
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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 68-69
(2009/07/03)
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- SUBSTITUTED 2-PHENYL-PYRIDINE DERIVATIVES
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The present invention relates to compounds of formula (I) wherein R1, R2, R4, R5, Ra, Rb, n, W and Z are as defined in the application, their preparation 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.
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Page/Page column 80
(2009/11/29)
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- A convenient procedure for the preparation of α-aminoallenes using a three-component reaction of aldehyde, carbamate and propargylsilane
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A three-component reaction is described using an aldehyde, a carbamate and trimethylpropargylsilane in the presence of a Lewis acid for the production in moderate to good yield of α-allenyl amines. The reaction is applicable to aromatic or aliphatic aldehydes. The obtained α-aminoallenes are transformed into Δ3-pyrrolidines or amino acids by using the reactivity of the cumulene function.
- Billet, Manuella,Schoenfelder, Angèle,Klotz, Philippe,Mann, André
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p. 1453 - 1456
(2007/10/03)
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- Lipase-catalyzed enantioselective acylation of prochiral 2-(ω)-phosphono)alkyl-1,3-propanediols: Application to the enantioselective synthesis of ω-phosphono-α-amino acids
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Lipase PS catalyzed acetylation of prochiral 2-(ω-phosphono)alkyl-1,3-propanediols 1a-c was found to proceed with high enantioselectivity. The applications of phosphonic chirons 2a-c thus obtained were illustrated by the stereocontrolled synthesis of ω-phosphono-α-amino acids such as L-AP-3, L-AP-4, and N-Boc-L-F2Pab(OEt)2-OH.
- Yokomatsu, Tsutomu,Sato, Mutsumi,Shibuya, Shiroshi
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p. 2743 - 2754
(2007/10/03)
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- Synthesis and Separation of a Diastereomeric Pair of Phosphonopeptide Inhibitors of the Cyclic AMP-Dependent Protein Kinase Catalytic Subunit
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In this paper we report the establishment of a novel procedure to synthesize a nonhydrolyzable phosphonopeptide dead-end inhibitor of the catalytic subunit of cAMP-dependent protein kinase.This procedure has been optimized to maximize the peptide yield and gives a diastereomeric pair of heptapeptides that can be separed on a C-18 reverse phase HPLC column.The two peptides have been characterized by NMR and the ability of these peptides to inhibit the reaction of the catalytic subunit of cAMP-dependent protein kinase.Peptide A has a dissociation constant of 9 micromolar, and is a 10-fold better inhibitor as compared to peptide B.On the basis of this 10-fold greater inhibition afforded by peptide A, this peptide is assigned the all L-form configuration.It is expected that this procedure can easily be adapted to synthesize a variety of different peptide inhibitors which involve a nonhydrolyzable phosphate on an amino acid.
- Yang, Chunhua,,Qamar, Raheel,Norton, Scott J.,Cook, Paul F.,Minter, David E.
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p. 1919 - 1926
(2007/10/02)
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- Synthesis of Optically Active 2-(tert-Butyloxycarbonylamino)-4-dialkoxyphosphorylbutanoate Protected Isosteres of O-Phosphonoserine for Peptide Synthesis
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The preparation of (S)-2-(tert-butoxycarbonylamino)-4-dialkoxyphosphorylbutanoate from (S)-aspartic acid is described.
- Valerio, R. M.,Alewood, P. F.,Johns, R. B.
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p. 786 - 789
(2007/10/02)
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