- An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins
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A glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. Here we describe the development of glucose cleavable linkers based on hydrazone and thiazolidine structures. We developed linkers with low levels of spontaneous hydrolysis but increased level of hydrolysis with rising concentrations of glucose, which demonstrated their glucose responsiveness in vitro. Lipidated hydrazones and thiazolidines were conjugated to the LysB29 side-chain of HI by pH-controlled acylations providing GRIs with glucose responsiveness confirmed in vitro for thiazolidines. Clamp studies showed increased glucose infusion at hyperglycemic conditions for one GRI indicative of a true glucose response. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.
- Mannerstedt, Karin,Mishra, Narendra Kumar,Engholm, Ebbe,Lundh, Morten,Madsen, Charlotte S.,Pedersen, Philip J.,Le-Huu, Priska,Pedersen, S?ren L.,Buch-M?nson, Nina,Borgstr?m, Bj?rn,Brimert, Thomas,Fink, Lisbeth N.,Fosgerau, Keld,Vrang, Niels,Jensen, Knud J.
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supporting information
p. 3166 - 3176
(2021/01/21)
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- Discovery of histone deacetylase 8 selective inhibitors
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We have developed an efficient method for synthesizing candidate histone deacetylase (HDAC) inhibitors in 96-well plates, which are used directly in high-throughput screening. We selected building blocks having hydrazide, aldehyde and hydroxamic acid functionalities. The hydrazides were coupled with different aldehydes in DMSO. The resulting products have the previously identified 'cap/linker/biasing element' structure known to favor inhibition of HDACs. These compounds were assayed without further purification. HDAC8-selective inhibitors were discovered from this novel collection of compounds.
- Tang, Weiping,Luo, Tuoping,Greenberg, Edward F.,Bradner, James E.,Schreiber, Stuart L.
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supporting information; experimental part
p. 2601 - 2605
(2011/06/22)
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- COMPOUNDS USEFUL IN THE TREATMENT OF INFLAMMATORY DISEASES
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There are provided according to the invention, novel compounds of formula (I)wherein R, R, R, R, Rand Rare as defined in the specification, processes for preparing them, formulations containing them and their use in therapy for the treatment of inflammatory diseases.
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- Acylguanidine derivatives as inhibitors of bone resorption and as vitronectin receptor antagonists
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The present invention relates to acylguanidine derivatives of formula (I) in which R1, R2, R4, R5, R6, A, m and n have the meanings indicated in the patent claims, their physiologically tolerable salt
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- A simple method for the preparation of monomethyl esters of dicarboxylic acids by selective esterification of the nonconjugated carboxyl group in the presence of an aromatic or conjugated carboxyl group
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Various dicarboxylic acids have been converted selectively into monomethyl esters in which the nonconjugated carboxyl group is selectively esterified in the presence of an aromatic or conjugated carboxyl group at room temperature (~ 25-27°C) in methanol using a catalytic amount of thionyl chloride.
- Ram, Ram N.,Meher, Nabin Kumar
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p. 282 - 283
(2007/10/03)
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- 5-membered heterocycles, medicaments containing these compounds, their use and processes for their preparation
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5-Membered heterocyclic compounds, of which the following compounds are exemplary: (a) 4-??trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-1-(4-piperidyl)imidazole, (b) 5-??trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-4-methyl-2-(4-piperidyl)-1,3-thiazole, (c) 5-??4-(carboxymethoxy)phenyl!aminocarbonyl!-4-methyl-2-(4-piperidyl)-1,3-thiazole, (d) 5-??trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole, (e) 5-??4-(carboxymethoxy)phenyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole, (f) 5-??trans-4-(carboxymethoxy)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole, (g) 5-??4-(carboxymethoxy)phenyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole, (h) 5-??trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole, and (i) 4-??trans-4-carboxycyclohexyl!aminocarbonyl!-1-?2-(4-piperidyl)ethyl!imidazole. These are useful for the treatment or prevention of illnesses in which relatively small or relatively large cell aggregates occur or cell-matrix interactions play a part.
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- Use of Phosphorus Pentoxide. Preparation of Half-esters through Selective Esterification
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Methyl 2-,3-,4-carboxyphenylacetate and methyl 2-,3-,4-carboxyphenoxyacetate have been prepared through selective esterification of the aliphatic carboxylic acid function of the corresponding dicarboxylic acids using a mixture of phosphorus pentoxide (1 part), anhydrous copper sulphate (5 parts) and anhydrous sodium sulphate (5 parts).All the isomeric half-esters have been prepared through partial hydrolysis of the corresponding dimethylesters.
- Banerjee, Amalendu,Adak, Mohini Mohan,Das, Sankar,Banerjee, Santa,Sengupta, Saumitra
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- α-Amino ketone derivatives
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The invention concerns α-aminoacyl derivatives of phenyl-, phenoxy-, thiophenoxy- and phenylsulphinylalkanoic acids together with their amides, esters and pharmaceutically acceptable salts; processes for their preparation; and pharmaceutical compositions for therapeutic use in inhibiting the formation of thrombi and also in reducing the persistence of thrombi formed in the blood of warm blooded animals. Representative compounds of the invention are methyl 4-(aminoacetyl)phenoxyacetate, 4-(aminoacetyl)phenoxyacetic acid and methyl 4-(aminoacetyl)-thiophenoxyacetate, preferably as their hydrochlorides.
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