- Tetrahydroimidazo[4,5-c]pyridine-based inhibitors of porphyromonas gingivalis glutaminyl cyclase
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Periodontitis is a severe yet underestimated oral disease. Since it is linked to several systemic diseases, such as diabetes, artheriosclerosis, and even Alzheimer’s disease, growing interest in treating periodontitis has emerged recently. The major cause of periodontitis is a shift in the oral microbiome. A keystone pathogen that is associated with this shift is Porphyromonas gingivalis. Hence, targeting P. gingivalis came into focus of drug discovery for the development of novel antiinfective compounds. Among others, glutaminyl cyclases (QCs) of oral pathogens might be promising drug targets. Here, we report the discovery and structure–activity relationship of a novel class of P. gingivalis QC inhibitors according to a tetrahydroimidazo[4,5-c]pyridine scaffold. Some compounds exhibited activity in the lower nanomolar range and thus were further characterized with regard to their selectivity and toxicity.
- Buchholz, Mirko,J?nckel, Nadine,Rahfeld, Jens-Ulrich,Ramsbeck, Daniel,Strich, Stefanie,Taudte, Nadine
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- BACTERIAL GLUTAMINYL CYCLASES AND INHIBITORS THEREOF FOR USE IN THE TREATMENT OF PERIODONTITIS
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The present invention relates to bacterial glutaminyl cyclases and inhibitors thereof for use in the treatment of periodontitis and related conditions, and provides a bacterial glutaminyl cyclase (bacQC); an antibody which recognizes the bacQC, a method for identifying an inhibitor of the bacQC; a compound according to Formula (I); a pharmaceutical composition comprising a bacQC inhibitor compound; a bacQC inhibitor compound and/or a pharmaceutical composition for use in a method for treatment of the human or animal body, for use in a method for therapy or prophylaxis of a bacterial infection, and for use in a method for therapy and/or prophylaxis of an acute, chronic or recurrent periodontal disease.
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Page/Page column 32
(2018/06/22)
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- PRMT5 INHIBITORS AND USES THEREOF
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Described herein are compounds of Formula (A), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof:wherein Y1 is of formula (?) or formula (y):Ring Y is a 5- to 6-membered heteroaryl ring; and V4, V5, Rx, x, y, and n are as defined herein. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
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Paragraph 00713; 00714
(2016/04/20)
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- Synthesis and structure based optimization of novel Akt inhibitors
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Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced pot
- Lippa, Blaise,Pan, Gonghua,Corbett, Matthew,Li, Chao,Kauffman, Goss S.,Pandit, Jayvardhan,Robinson, Shaughnessy,Wei, Liuqing,Kozina, Ekaterina,Marr, Eric S.,Borzillo, Gary,Knauth, Elisabeth,Barbacci-Tobin, Elsa G.,Vincent, Patrick,Troutman, Merin,Baker, Deborah,Rajamohan, Francis,Kakar, Shefali,Clark, Tracey,Morris, Joel
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body text
p. 3359 - 3363
(2009/04/05)
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- 4,5,6,7-Tetrahydroimidazo-[4,5-c]-pyridine derivatives
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New 4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine derivatives are disclosed, and more particularly derivatives of Formula I STR1 where R1 is hydrogen or an alkyl having from 1 to 4 carbon atoms; R2 is hydrogen, an alkyl having from 1 to 4 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, phenyl or a heterocycle; R3 is hydrogen, a saturated or unsaturated straight or branched alkyl having from 1 to 6 carbon atoms, a cycloalkyl having from 3 to 6 carbon atoms, benzoyl or phenyl; and X is O, S or NR4 where R4 is hydrogen, an alkyl having from 1 to 4 carbon atoms, cyano, amino, nitro or acylamino; Or pharmaceutically acceptable acid addition salts thereof. Also disclosed is a process of preparing these compounds which comprises condensing an appropriate 4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine with an appropriate alkyl isocyanate, alkyl isothiocyanate or substituted S-methyl thiourea, preferably in a solvent such as ethanol, acetonitrile or dioxane, usually under reflux for from 4 to 12 hours. The products can be isolated by crystallization as free bases or as salts of pharmaceutically acceptable acids. The new compounds have proved to be well tolerated and to inhibit both the number of experimental ulcers and the gastric secretion in experimental animals. Thus, they should prove useful in the therapy of gastric and duodenal ulcers in man.
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