- Synthesis of the suicide substrate D-propargylglycine stereospecifically labelled with deuterium and investigation of its oxidation by D-amino acid oxidase
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Stereospecifically deuteriated samples of D-propargylglycine 1 have been prepared by reaction of the labelled Pmc-protected aziridine free acids 22 with a lithium acetylide followed by deprotection. These samples have been used to show that D-amino acid oxidase, in converting D-propargylglycine to the lactone 5, deprotonates C-3 in a non-stereospecific manner. This strongly supports the idea that non-enzymic deprotonation is a key step in the formation of this compound.
- Church, Nicola J.,Young, Douglas W.
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Read Online
- Total synthesis and activity of the metallo-β-lactamase inhibitor aspergillomarasmine A
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Resistance to β-lactam antibiotics is mediated primarily by enzymes that hydrolytically inactivate the drugs by one of two mechanisms: serine nucleophilic attack or metal-dependent activation of a water molecule. Serine β-lactamases are countered in the c
- Koteva, Kalinka,King, Andrew M.,Capretta, Alfredo,Wright, Gerard D.
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Read Online
- RAS INHIBITORS
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The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.
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Paragraph 1474-1475
(2021/05/07)
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- COVALENT RAS INHIBITORS AND USES THEREOF
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The disclosure features compounds, or pharmaceutically acceptable salts thereof, alone and in combination with other therapeutic agents, pharmaceutical compositions, and protein conjugates thereof, capable of modulating biological processes including Ras, and their uses in the treatment of cancers.
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Page/Page column 255
(2021/06/04)
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- Aryl substituted aminotetrahydropyran compound and use thereof
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The invention relates to an aryl substituted aminotetrahydropyran compound and use thereof, and further relates to a pharmaceutical composition comprising the compound. The compound or pharmaceuticalcomposition provided by the invention can be used as a dipeptidyl peptidase-IV (DPP-IV) inhibitor.
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Paragraph 0368; 0374; 0375; 0376
(2019/07/04)
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- Studies on the synthesis of orthogonally protected azalanthionines, and of routes towards β-methyl azalanthionines, by ring opening of N-activated aziridine-2-carboxylates
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Orthogonally protected azalanthionines were successfully synthesised by the ring-opening of N-activated aziridine-2-carboxylates with protected diaminopropanoic acids (DAPs). The required DAPs were also prepared by ring-opening of N-activated aziridine-2-carboxylates with para- methoxybenzylamine, but it was found that the choice of aziridine protecting groups dictated both the success of the reaction as well as the regioselectivity of the isolated products. Attempts to extend the methodology to the preparation of the more sterically demanding β-methyl azalanthionines have, so far, been unsuccessful.
- O'Brien, Keith,ó Proinsias, Keith,Kelleher, Fintan
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supporting information
p. 5082 - 5092
(2014/07/08)
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- Synthesis of orthogonally protected azalanthionines (lanazanines) by sequential ring-opening of N-substituted aziridine 2-carboxylates
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Orthogonally protected azalanthionines (lanazanines, 4-azadiaminopimelic acids or β-aminoalaninoalanines) have been synthesised in good yields by the ring-opening of N-protected aziridine 2-carboxylates with suitably protected diaminopropanoic acids (DAPs
- O'Brien, Keith,ó Proinsias, Keith,Kelleher, Fintan
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p. 2395 - 2397
(2013/06/27)
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- Discovery of a new class of glucosylceramide synthase inhibitors
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A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.
- Koltun, Elena,Richards, Steven,Chan, Vicky,Nachtigall, Jason,Du, Hongwang,Noson, Kevin,Galan, Adam,Aay, Naing,Hanel, Art,Harrison, Amanda,Zhang, Jeff,Won, Kwang-Ai,Tam, Danny,Qian, Fawn,Wang, Tao,Finn, Patricia,Ogilvie, Kathleen,Rosen, Jon,Mohan, Raju,Larson, Christopher,Lamb, Peter,Nuss, John,Kearney, Patrick
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scheme or table
p. 6773 - 6777
(2011/12/05)
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- The structure?activity relationship of the 3-Oxy site in the anticonvulsant (R)- N -benzyl 2-acetamido-3-methoxypropionamide
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Lacosamide ((R)-N-benzyl 2-acetamido-3-methoxypropionamide, (R)-1) is a low molecular weight anticonvulsant recently introduced in the United States and Europe for adjuvant treatment of partial-onset seizures in adults. In this study, we define the structure?activity relationship (SAR) for the compound's 3-oxy site. Placement of small nonpolar, nonbulky substituents at the 3-oxy site provided compounds with pronounced seizure protection in the maximal electroshock (MES) seizure test with activities similar to (R)-1. The anticonvulsant activity loss that accompanied introduction of larger moieties at the 3-oxy site in (R)-1 was offset, in part, by including unsaturated groups at this position. Our findings were similar to a recently reported SAR study of the 4?-benzylamide site in (R)-1 (J. Med. Chem. 2010, 53, 1288 ?1305). Together, these results indicate that both the 3-oxy and 4?-benzylamide positions in (R)-1 can accommodate nonbulky, hydrophobic groups and still retain pronounced anticonvulsant activities in rodents in the MES seizure model.
- Morieux, Pierre,Salomé, Christophe,Park, Ki Duk,Stables, James P.,Kohn, Harold
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body text
p. 5716 - 5726
(2010/10/03)
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- Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group
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We have advanced a novel strategy to search for lacosamide ((R)-1) targets in the brain proteome where protein binding is expected to be modest. Our approach used lacosamide agents containing "affinity bait" (AB) and "chemical reporter" (CR) units. The affinity bait moiety is designed to irreversibly react with the target, and the CR group permits protein detection and capture. In this study, we report the preparation and evaluation of (R)-N-(4-azido)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-3) and show that this compound exhibits potent anticonvulsant activities in the MES seizure model in rodents. We compared the utility of (R)-3 with its isostere, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-2), in proteomic studies designed to identify potential (R)-1 targets. We showed that despite the two-fold improved anticonvulsant activity of (R)-3 compared with (R)-2, (R)-2 was superior in revealing potential binding targets in the mouse brain soluble proteome. The difference in these agents' utility has been attributed to the reactivity of the affinity baits (i.e., (R)-2: aryl isothiocyanate moiety; (R)-3: photoactivated aryl azide intermediates) in the irreversible protein modification step, and we conclude that this factor is a critical determinant of successful target detection where ligand (drug) binding is modest. The utility of (R)-2 and (R)-3 in in situ proteome studies is explored.
- Park, Ki Duk,Stables, James P.,Liu, Rihe,Kohn, Harold
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scheme or table
p. 2803 - 2813
(2010/08/21)
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- Lacosamide isothiocyanate-based agents: Novel agents to target and identify lacosamide receptors
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(R)-Lacosamide ((R)-2, (R)-N-benzyl 2-acetamido-3-methoxypropionamide) has recently gained regulatory approval for the treatment of partial-onset seizures in adults.Whole animal pharmacological studies have documented that (R)-2 function is unique. A robust strategy is advanced for the discovery of interacting proteins associated with function and toxicity of (R)-2 through the use of (R)-2 analogues, 3, which contain "affinity bait (AB)" and "chemical reporter (CR)" functional groups. In 3, covalent modification of the interacting proteins proceeds at the AB moiety, and detection or isolation of the selectively captured protein occurs through the bioorthogonal CR group upon reaction with an appropriate probe. We report the synthesis, pharmacological evaluation, and interrogation of the mouse soluble brain proteome using 3 where the AB group is an isothiocyanate moiety. One compound, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy) propionamide ((R)-9), exhibited excellent seizure protection in mice, and like (R)-2, anticonvulsant activity principally resided in the (R)-stereoisomer. Several proteins were preferentially labeled by (R)-9 compared with (S)-9, including collapsin response mediator protein 2. 2009 American Chemical Society.
- Ki, Duk Park,Morieux, Pierre,Salomé, Christophe,Cotten, Steven W.,Reamtong, Onrapak,Eyers, Claire,Gaskell, Simon J.,Stables, James P.,Liu, Rihe,Kohn, Harold
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supporting information; experimental part
p. 6897 - 6911
(2010/04/24)
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- Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives
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Lacosamide has been submitted for regulatory approval in the United States and Europe for the treatment of epilepsy. Previous synthetic methods did not permit the elaboration of the structure-activity relationship (SAR) for the 3-oxy site in lacosamide. We report an expedient five-step stereospecific synthesis for N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide analogs beginning with d-serine methyl ester. The procedure incorporated alkyl (e.g. methyl, primary, secondary, and tertiary) and aryl groups at this position. The SAR for the 3-oxy site showed maximal activity in animal seizure models for small 3-alkoxy substituents.
- Morieux, Pierre,Stables, James P.,Kohn, Harold
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experimental part
p. 8968 - 8975
(2009/04/06)
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- Microwave-assisted ring-opening of activated aziridines with resin-bound amines
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(Chemical Equation Presented) This paper describes the first study of nucleophilic ring-opening of nosylamide-activated aziridines under microwave irradiation conditions in solid-phase synthesis (SPS). The effects of solvent, temperature, reaction time, a
- Crestey, Francois,Witt, Matthias,Frydenvang, Karla,Staerk, Dan,Jaroszewski, Jerzy W.,Franzyk, Henrik
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p. 3566 - 3569
(2008/09/20)
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- DPP-IV INHIBITOR INCLUDING BETA-AMINO GROUP, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME FOR PREVENTING AND TREATING A DIABETES OR AN OBESITY
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The present invention provides a novel heterocyclic compound containing a beta-amino group, a method for preparing the same, and a pharmaceutical composition comprising the same heterocyclic compound or a pharmaceutically acceptable salt thereof as an act
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Page/Page column 12; 16
(2008/12/08)
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- Versatile Synthesis of Stereospecifically Labelled D-Amino Acids via Labelled Aziridines - Preparation of (2R,3S)-- and (2R,3R)--Serine; (2S,2'S,3S,3'S)-- and (2S,2'S,3R,3'R)--Cystine; and (2S,3S)- and (2S,3R)--β-Chloroalanine
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Stereospecifically β-labelled protected 2-carboxyaziridines 2, with the stereochemistry of a D-amino acid at C-2, have been prepared by a chemicoenzymic synthesis.Preparation of the labelled malates 5, by hydration of fumaric acid using the enzyme fumarase or by amination with aspartase followed by nitrosation, was followed by conversion into the isoserines 3, by a process involving Curtius rearrangement with retention of stereochemistry at the chirally labelled primary centre.Protection and ring closure gave the aziridines 2, which, on ring opening with the appropriate nucleophiles and deprotection, gave stereospecifically labelled samples of D-serine 16, D-cystine 20 and β-chloro-D-alanine 22.
- Axelsson, B. Svante,O'Toole, Kevin J.,Spencer, Philip A.,Young, Douglas W.
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p. 807 - 816
(2007/10/02)
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- Synthesis of Stereospecifically Labelled D-Prop-2-ynylglycine and Investigation of the Action of D-Amino Acid Oxidase
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Stereospecifically deuteriated samples of D-prop-2-ynylglycine 1 are synthesised by reaction of the labelled aziridines 13 with a carbon nucleophile followed by deprotection; incubation of these samples with D-amino acid oxidase indicates that, in formation of the lactone 5, deprotonation at C-3 is non-stereospecific, strongly supporting non-enzymatic deprotonation as a key step in the formation of this compound.
- Church, Nicola J.,Young, Douglas W.
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p. 943 - 944
(2007/10/02)
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- Candida cylindracea Lipase-Catalysed Hydrolysis of Methyl Aziridine-2-carboxylates and 2,3-dicarboxylates
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N-Substituted aziridine-2-carboxylates and 2,3-dicarboxylates have been resolved with good to excellent stereochemical purity by enzymatic hydrolysis catalysed by lipase from Candida cylindracea.
- Bucciarelli, Maria,Forni, Arrigo,Moretti, Irene,Prati, Fabio,Torre, Giovanni
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p. 3041 - 3046
(2007/10/02)
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