7 research outputs found
Glikoenzim-inhibítorok előállítása = Synthesis of glycoenzyme inhibitors
A szénhidrát alapú gyógyszerek kifejlesztésének egyik iránya a glikoenzimek gátlószereinek és szerkezet?hatás összefüggéseiknek (SAR) felderítése. A kutatás során glikozidázokat, amilázokat és glikogén foszforilázokat (GP) gátló cukorszármazékokat készítettünk, melyek - főképp antidiabetikus - terápiás célokra lehetnek alkalmasak. A GP első nanomólos glükózanalóg inhibitorait készítettük el N-beta-D-glükopiranozil-N'-szubsztituált karbamidok, analógjaik és származékaik szintézise során. Részletes SAR-t állítottunk fel új gátlószerek kifejlesztéséhez. Megfigyeltük e származékok kötődését a katalitikus helyen kívül az új allosztérikus helyhez is, és célzottan ide irányítható cukorvegyületeket készítettünk. A GP újabb nanomólos gátlószereit fedeztük fel glikopiranozilidén-spiro-oxadiazolok, -szulfahidantoinok, -tiazolonok, -imidazolonok és -oxatiazolok szintézisének vizsgálatakor. Egyes oxatiazolok az E. coli galaktozidáz millimólos inhibitorai. Az enzimatikusan szintetizált akarviozinil-izomaltozil-spiro-tiohidantoin a nyál amiláz akarbóznál négyszer jobb inhibitora. Sztereoszelektív módszerekkel anomer alfa-aminosavat tartalmazó di- és tripeptideket készítettünk. A 2,2,2-triklóretil-alapú védőcsoportok kemoszelektív lehasítását írtuk le redukcióra és savakra érzékeny csoportok mellett. Felkérésre több összefoglalót írtunk a GP gátlók tervezéséről és antidiabetikus alkalmazási lehetőségeikről. | Discovery of inhibitors of glycoenzymes and revealing their structure?activity relationship (SAR) is a principal trend in the development of carbohydrate based drugs. In our research sugar derivatives of therapeutic (mainly antidiabetic) potential inhibiting glycosidases, amylases, and glycogen phosphorylases (GP) were prepared. The first nanomolar glucose analog inhibitors of GP were obtained by syntheses of N-beta-D-glucopyranosyl-N'-substituted ureas, their analogs and derivatives. A detailed SAR was deduced for developing new inhibitors. Binding of these derivatives to the new allosteric site vs. the catalytic site of GP was observed, and sugar compounds to be diverted to this site were synthesized. Further novel nanomolar inhibitors of GP were found during investigation of syntheses for glycopyranosylidene-spiro-oxadiazoles, -sulfahydantoins, -thiazolones, -imidazolones, and -oxathiazoles. Some oxathiazoles are millimolar inhibitors of E. coli galactosidase. Acarviosinyl-isomaltosyl-spiro-thiohydantoin obtained by enzymatic synthesis proved a 4-fold better inhibitor of salivary amylase than acarbose. Di- and tripeptides containing anomeric alpha-amino acids were made by stereoselective methods. A chemoselective method was described for deprotection of 2,2,2-trichloroethyl based blocking groups next to reducible and acid sensitive functionalities. On invitation several reviews were written about design and possible antidiabetic utilization of GP inhibitors
Synthesis of N-(beta-D-glucopyranosyl) monoamides of dicarboxylic acids as potential inhibitors of glycogen phosphorylase
Synthesis of N-(beta-D-glucopyranosyl)- and N-(2-acetamido-2-deoxy-beta-D-glucopyranosyl) amides as inhibitors of glycogen phosphorylase
Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site
Novel-Type GABA<sub>B</sub> PAMs: Structure–Activity Relationship in Light of the Protein Structure
Selecting
a known HTS hit with the pyrazolo[1,5-a]pyrimidine
core, our project was started from CMPPE, and its optimization
was driven by a ligand-based pharmacophore model developed on the
basis of published GABAB positive allosteric modulators
(PAMs). Our primary goal was to improve the potency by finding new
enthalpic interactions. Therefore, we included the lipophilic ligand
efficiency (LLE or LipE) as an objective function in the optimization
that led to a carboxylic acid derivative (34). This lead
candidate offers the possibility to improve potency without drastically
inflating the physicochemical properties. Although the discovery of
the novel carboxyl feature was surprising, it turned out to be an
important element of the GABAB PAM pharmacophore that can
be perfectly explained based on the new protein structures. Rationalizing
the binding mode of 34, we analyzed the intersubunit
PAM binding site of GABAB receptor using the publicly available
experimental structures