- Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding
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Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.
- Deng, Hui,Kooijman, Sander,Van Den Nieuwendijk, Adrianus M. C. H.,Ogasawara, Daisuke,Van der Wel, Tom,Van Dalen, Floris,Baggelaar, Marc P.,Janssen, Freek J.,Van Den Berg, Richard J. B. H. N.,Den Dulk, Hans,Cravatt, Benjamin F.,Overkleeft, Herman S.,Rensen, Patrick C. N.,Van der Stelt, Mario
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supporting information
p. 428 - 440
(2017/04/26)
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- Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights to Realize the Enantioselective Synthesis of Piperazines
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An efficient and practical catalytic approach for the enantioselective synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions is described. Starting from ether-containing aminoalkyne substrates, a commercially available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is subsequently reduced using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η6-p-cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric excesses of >95%. A wide range of functional groups is tolerated. Substrate scope investigations suggest that hydrogen-bonding interactions between the oxygen in the backbone of the ether-containing substrate and the [(S,S)-Ts-DPEN] ligand of the Ru catalyst are crucial for obtaining high ee's. This insight led to a mechanistic proposal that predicts the observed absolute stereochemistry. Most importantly, this mechanistic insight allowed for the extension of this strategy to include N as an alternative hydrogen bond acceptor that could be incorporated into the substrate. Thus, the catalytic, enantioselective synthesis of 3-substituted piperazines is also demonstrated.
- Lau, Ying Yin,Zhai, Huimin,Schafer, Laurel L.
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p. 8696 - 8709
(2016/10/14)
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- An (R)-imine reductase biocatalyst for the asymmetric reduction of cyclic imines
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Although the range of biocatalysts available for the synthesis of enantiomerically pure chiral amines continues to expand, few existing methods provide access to secondary amines. To address this shortcoming, we have over-expressed the gene for an (R)-imine reductase [(R)-IRED] from Streptomyces sp. GF3587 in Escherichia coli to create a recombinant whole-cell biocatalyst for the asymmetric reduction of prochiral imines. The (R)-IRED was screened against a panel of cyclic imines and two iminium ions and was shown to possess high catalytic activity and enantioselectivity. Preparative-scale synthesis of the alkaloid (R)-coniine (90 % yield; 99 % ee) from the imine precursor was performed on a gram-scale. A homology model of the enzyme active site, based on the structure of a closely related (R)-IRED from Streptomyces kanamyceticus, was constructed and used to identify potential amino acids as targets for
- Hussain, Shahed,Leipold, Friedemann,Man, Henry,Wells, Elizabeth,France, Scott P.,Mulholland, Keith R.,Grogan, Gideon,Turner, Nicholas J.
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p. 579 - 583
(2015/03/05)
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- Stereoelectronic basis for the kinetic resolution of n-heterocycles with chiral acylating reagents
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The kinetic resolution of N-heterocycles with chiral acylating agents reveals a previously unrecognized stereoelectronic effect in amine acylation. Combined with a new achiral hydroxamate, this effect makes possible the resolution of various N-heterocycles by using easily prepared reagents. A transition-state model to rationalize the stereochemical outcome of this kinetic resolution is also proposed.
- Hsieh, Sheng-Ying,Wanner, Benedikt,Wheeler, Philip,Beauchemin, Andre M.,Rovis, Tomislav,Bode, Jeffrey W.
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supporting information
p. 7228 - 7231
(2014/06/23)
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- Catalytic asymmetric synthesis of substituted morpholines and piperazines
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Under two conditions: Hydroamination catalyzed by group 4 metals is featured in the modular and enantioselective synthesis of 3-substituted morpholines and the diastereoselective synthesis of 2,5-substituted piperazines. Copyright
- Zhai, Huimin,Borzenko, Andrey,Lau, Ying Yin,Ahn, Shin Hye,Schafer, Laurel L.
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supporting information
p. 12219 - 12223
(2013/02/23)
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- Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles
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The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.
- Hsieh, Sheng-Ying,Binanzer, Michael,Kreituss, Imants,Bode, Jeffrey W.
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supporting information
p. 8892 - 8894
(2012/11/07)
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- Catalytic kinetic resolution of cyclic secondary amines
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The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.
- Binanzer, Michael,Hsieh, Sheng-Ying,Bode, Jeffrey W.
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supporting information; experimental part
p. 19698 - 19701
(2012/01/13)
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- 1,2,4 TRIAZOLO [4, 3 -A] [1,5] BENZODIAZEPIN-5 (6H) -ONES AS AGONISTS OF THE CHOLECYSTOKININ-1 RECEPTOR (CCK-IR)
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This invention relates to CCK-1 R agonists of Formula (I) wherein R1-R5 and X are as defined in the specificiation, as well as pharmaceutical compositions containing the compounds and methods of use of the compounds and compositions. The compounds are useful in treating obesity, type 2 diabetes and associated diseases.
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Page/Page column 52-53
(2010/07/02)
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- Diastereopure Preparation of α-Benzotriazolyl 1-Azacycloalka[2,1-b] [1,3]-oxazines and their Application as Versatile Chiral Precursors
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A group of diastereopure α-benzotriazolyl 1-azacycloalka[2,1-b][1,3] oxazines were prepared from non-racemic Betti base and they were employed as the versatile precursors for the preparation of chiral ligands and chiral substituted azacyclics with signifi
- Xu, Xuenong,Lu, Jun,Li, Rui,Ge, Zongming,Dong, Yanmei,Hu, Yuefei
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p. 122 - 124
(2007/10/03)
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