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Immunomodulatory Drugs in Type I Diabetes
Published in George S. Eisenbarth, Immunotherapy of Diabetes and Selected Autoimmune Diseases, 2019
Kolb Hubert, Schmidt Michael, Kiesel Ulrich
In the low-dose streptozotocin diabetes model several different radical scavengers have been tried (I. Flechner, U. Kiesel, H. Kolb, manuscript in preparation47. Care was taken to start administration only after the last streptozotocin injection in order to avoid interaction with the beta cell toxin. Neither cysteamine (two trials with 45 and 150 mg/kg), benzamidine (50 mg/kg) nor butylated hydroxytoluene (120 mg/kg) affected the course of the disease.
Tumor Cell Invasion In Vitro in Syngeneic and Heterologous Systems
Published in Rolf Bjerkvig, Spheroid Culture in Cancer Research, 2017
Monolayer cocultures have been studied between adenoma and colon carcinoma cells,23 in which the carcinoma cells caused detachment of the adenoma cells. The inhibition of urokinase by treatment with benzamidine inhibited the destruction of the adenoma colonies, whereas addition of a tumor promoter (12-O-tetradecanoylphorbol-13-acetate) increased the destructive effects of the tumor cells.
Crystallization of Purple Bacterial Antenna Complexes
Published in Hartmut Michel, Crystallization of Membrane Proteins, 1991
Richard J. Cogdell, Kevin J. Woolley, Linda A. Ferguson, Deborah J. Dawkins
We have subsequently tried a range of other small molecules to see if they would act as effective small amphiphiles. Our conclusions from these studies are shown in Table 4. So far benzamidine hydrochloride (better known as a protease inhibitor) has proved to be the most useful. Figure 4 shows some of the crystal forms that we have obtained using the various amphiphiles with the B800-850-complex from Rps. acidophila.
Absorption, distribution, metabolism, and excretion of radiolabeled naldemedine in healthy subjects
Published in Xenobiotica, 2019
Shuichi Ohnishi, Kazuya Fukumura, Ryuji Kubota, Toshihiro Wajima
Mean recoveries of total radioactivity of 92% and 85% were obtained following dosing with [oxadiazole-14C]- and [carbonyl-14C]-naldemedine, respectively (Figure 4). The degree of renal elimination was greater than fecal elimination following administration of [oxadiazole-14C]-naldemedine (57.3% vs. 34.8%, respectively). Conversely, fecal elimination was greater than renal elimination following administration of [carbonyl-14C]-naldemedine (64.3% vs. 20.4%, respectively; Figure 4). With both radiolabels, approximately 20% of naldemedine underwent renal elimination. The main difference in the degree of renal and fecal elimination was attributed to the contribution from radiolabeled benzamidine in urine for [oxadiazole-14C]-naldemedine. Although benzamidine was not detected in plasma, it was the major metabolite in urine and accounted for approximately 30% of the administered dose of [oxadiazole-14C]-naldemedine (Table 4).
Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract – A review of patent literature
Published in Expert Opinion on Therapeutic Patents, 2020
Alexandre Murza, Sébastien P. Dion, Pierre-Luc Boudreault, Antoine Désilets, Richard Leduc, Éric Marsault
Steinmetzer and colleagues reported a series of (S)-3-(3-oxo-2-(phenylsulfonamido)-3-(piperidin-1-yl)propyl)benzimidamide derivatives (WO2013014074) [79] that inhibit TMPRSS2. Using the purified recombinant protease domain of TMPRSS2, 45 compounds were assessed for their inhibitory effect, with Ki values ranging from 0.93 nM for compound 1Figure 4A to 25,000 nM for other analogues. On the sulfonamide scaffold, R1 is substituted with diverse aromatic groups and amines whereas R2 is derived with arylureas, amines, esters, and carboxylic acids. Interestingly, the presence of an amine group on R2 provides the most potent inhibitors of TMPRSS2 in this series, whereas the R1 position appears less critical. In a related article, analogue 1 reduced the replication of H1N1 and H3N2 influenza viruses in Calu-3 cells [48]. Importantly, according to this publication, Ki values against TMPRSS2 strongly correlate with Ki values against matriptase, which can be attributed to the high sequence homology between the two proteases (41% for the catalytic domain). Based on this chemical template, another patent was released the same year on matriptase inhibitors (US8569313) [80]. Another set of modifications, especially on position R1, led to the identification of compound 2 with a very low Ki of 0.069 nM in an in vitro matriptase inhibition assay using a Gly-Arg-pNA substrate and recombinant enzyme Figure 4A. The benzamidine group (R3) substituted by hydroxyl or methoxy groups (pro-drugs) displays no inhibition. The benzylamine moiety leads to 50–100-fold reduction in Ki. Finally, an amine group on position R1 appears important to maintain inhibition.
Linkers in fragment-based drug design: an overview of the literature
Published in Expert Opinion on Drug Discovery, 2023
Dylan Grenier, Solène Audebert, Jordane Preto, Jean-François Guichou, Isabelle Krimm
A pioneering example was reported by Burgess et al. [29] with the dimerization of a benzamidine fragment bound to two adjacent active sites of the tryptase enzyme. The initial benzamidine fragment was substituted in the para position to introduce an acidic function that could then react with an amine-containing linker. A long linker (21 bonds) also containing aromatic rings and an ether function was required to bridge the two fragments and obtain picomolar inhibitors of the enzyme.