6257-49-4Relevant academic research and scientific papers
Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics
Hillisch, Alexander,Gericke, Kersten M.,Allerheiligen, Swen,Roehrig, Susanne,Schaefer, Martina,Tersteegen, Adrian,Schulz, Simone,Lienau, Philip,Gnoth, Mark,Puetter, Vera,Hillig, Roman C.,Heitmeier, Stefan
supporting information, p. 12574 - 12594 (2020/11/13)
Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.
Highly enantioselective carbene insertion into N–H bonds of aliphatic amines
Li, Mao-Lin,Yu, Jin-Han,Li, Yi-Hao,Zhu, Shou-Fei,Zhou, Qi-Lin
, p. 990 - 994 (2019/11/28)
Aliphatic amines strongly coordinate, and therefore easily inhibit, the activity of transition-metal catalysts, posing a marked challenge to nitrogen-hydrogen (N–H) insertion reactions. Here, we report highly enantioselective carbene insertion into N–H bo
Manganese catalyzed reductive amination of aldehydes using hydrogen as a reductant
Wei, Duo,Bruneau-Voisine, Antoine,Valyaev, Dmitry A.,Lugan, No?l,Sortais, Jean-Baptiste
supporting information, p. 4302 - 4305 (2018/05/03)
A one-pot two-step procedure was developed for the alkylation of amines via reductive amination of aldehydes using molecular dihydrogen as a reductant in the presence of a manganese pyridinyl-phosphine complex as a pre-catalyst. After the initial condensation step, the reduction of imines formed in situ is performed under mild conditions (50-100 °C) with 2 mol% of catalyst and 5 mol% of tBuOK under 50 bar of hydrogen. Excellent yields (>90%) were obtained for a large combination of aldehydes and amines (40 examples), including aliphatic aldehydes and amino-alcohols.
New C2-symmetric chiral phosphinite ligands based on amino alcohol scaffolds and their use in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones
Durap, Feyyaz,Aydemir, Murat,Elma, Duygu,Baysal, Akin,Turgut, Yilmaz
, p. 363 - 371 (2013/08/25)
Asymmetric transfer hydrogenation processes of ketones with chiral molecular catalysts are attracting increasing interest from synthetic chemists due to their operational simplicity. C2-symmetric catalysts have also received much attention and been used in many reactions. A series of new chiral C2-symmetric bis(phosphinite) ligands has been prepared from corresponding amino acid derivated amino alcohols or (R)-2-amino-1-butanol through a three- or four-step procedure. Their structures have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy and elemental analysis. 1H-31P NMR, DEPT, 1H-13C HETCOR or 1H-1H COSY correlation experiments were used to confirm the spectral assignments. In situ prepared ruthenium catalytic systems were successfully applied to ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives by iso-PrOH. Under optimized conditions, these chiral ruthenium catalyst systems serve as catalyst precursors for the asymmetric transfer hydrogenation of acetophenone derivatives in iso-PrOH and act as good catalysts, giving the corresponding optical secondary alcohols in 99% yield and up to 79% ee.
Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors
Medina, Jesús R.,Becker, Christopher J.,Blackledge, Charles W.,Duquenne, Celine,Feng, Yanhong,Grant, Seth W.,Heerding, Dirk,Li, William H.,Miller, William H.,Romeril, Stuart P.,Scherzer, Daryl,Shu, Arthur,Bobko, Mark A.,Chadderton, Antony R.,Dumble, Melissa,Gardiner, Christine M.,Gilbert, Seth,Liu, Qi,Rabindran, Sridhar K.,Sudakin, Valery,Xiang, Hong,Brady, Pat G.,Campobasso, Nino,Ward, Paris,Axten, Jeffrey M.
experimental part, p. 1871 - 1895 (2011/05/30)
Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.
Pyridine containing chiral macrocycles: Synthesis and their enantiomeric recognition for amino acid derivatives
Deniz, Pinar,Turgut, Yilmaz,Togrul, Mahmut,Hosgoren, Halil
scheme or table, p. 6227 - 6232 (2011/09/19)
Four novel C2-symmetric enantiomerically pure, chiral pyridine-18-crown-6 type macrocycles containing lipophilic chains at the stereogenic centers were prepared. The enantioselectivity of the new ligands toward the enantiomers of d-,l-amino acid methyl ester derivatives were also determined by 1H NMR titration method. These novel macrocycles have been showed to be strong complexing agents for d- and l-amino acid methyl ester hydrochloride salts (with Kass up to 13590 M-1 and G 0 up to 23.3 kJ mol-1 and selectivity ratio: 80:20) by 1H NMR titration methods. These macrocyclic hosts exhibited enantioselective binding towards the d-enantiomer of valine methyl ester hydrochloride with Kd/Kl up to 5.08 in CDCl3 with 0.25% CD3OD.
Synthesis of C2-symmetric chiral amino alcohols: Their usage as organocatalysts for enantioselective opening of epoxide ring
Turgut, Yilmaz,Aral, Tarik,Karakaplan, Mehmet,Deniz, Pinar,Hosgoren, Halil
scheme or table, p. 3365 - 3377 (2011/01/04)
A series of -amino alcohols derivatives were synthesized from (R)-2-amino-1-butanol and (S)-1,2-propanediol, and they have been used as organocatalaysts in the racemic ring opening of epoxide in good yields with high enantiomeric excess (up to 97%). Copyright
Stereocontrolled synthesis of 3-substituted azetidinic amino acids
Sivaprakasam, Mangaleswaran,Couty, Fran?ois,Evano, Gwilherm,Srinivas,Sridhar,Rao, K. Rama
, p. 781 - 785 (2007/10/03)
A set of enantiomerically pure N-disubstituted β-amino alcohols was chlorinated by treatment with thionyl chloride. This reaction gave a mixture of regioisomeric chlorides that could be equilibrated to the more stable regioisomer by heating in DMF. The chlorides thus obtained were engaged in an intramolecular anionic ring-closure and gave access to fully protected enantio- and diastereomerically pure 2,3-cis-disubstituted azetidinic amino acids. One of the latter was deprotected and included in a short peptide sequence. Georg Thieme Verlag Stuttgart.
Synthesis of chiral monoaza-15-crown-5 ethers from a chiral amino alcohol and enantiomeric recognition of potassium and sodium salts of amino acids
Togrul, Mahmut,Askin, Muzaffer,Hosgoren, Halil
, p. 2771 - 2777 (2007/10/03)
The enantiomeric recognition of chiral monoaza-crown ethers for amino acids as their sodium and potassium salts has been investigated by UV-vis. The highest discrimination was observed for TrpK (d/l = 6.47). The reversed enantioselectivity of chiral monoaza-crown ether II was observed for TrpK.
Combining Magnetic Resonance Spectroscopies, Mass Spectrometry, and Molecular Dynamics: Investigation of Chiral Recognition by 2,6-di-O-Methyl-β-cyclodextrin
Franchi, Paola,Lucarini, Marco,Mezzina, Elisabetta,Pedulli, Gian Franco
, p. 4343 - 4354 (2007/10/03)
EPR spectroscopy has been employed to investigate the formation of complexes between heptakis-(2,6-O-dimethyl)-β-cyclodextrin (DM-β-CD) and different enantiomeric pairs of chiral nitroxides of general structure PhCH2N(O·)CH(R)R′. Accurate equilibrium measurements of the concentrations of free and included radicals afforded the binding constant values for these nitroxides. The relationship between the stereochemistry of the DM-β-CD complexes and the thermodynamics of complexation was elucidated by correlating EPR data with 1H-1H NOE measurements carried out on the complexes between DM-β-CD and the structurally related amine precursors of nitroxides. NOE data suggested that inclusion of the stereogenic center in the DM-β-CD cavity occurs only when the R substituent linked to the chiral carbon contains an aromatic ring. For these types of complexes, molecular dynamics simulation indicated that the depth of penetration of the stereogenic center into the cyclodextrin cavity is determined by the nature of the second substituent (R′) at the asymmetric carbon and is responsible for the observed chiral selectivity. Analysis of mass spectra showed that, for the presently investigated amines, electrostatic external adducts of CDs with protonated amines are detected by ESI-MS.
