A group of tri and tetrasubstituted urea derivatives have been found to be hH(3)-antagonists. The most potent compounds were found in the class of (piperazine-1-yl)-(piperidine-1-yl)-methanones which in addition showed negligible hERG inhibition.
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Carbonic anhydrases activation with 3-amino-1H-1,2,4-triazole-1-carboxamides: Discovery of subnanomolar isoform II activators.
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Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy. Electronic address:
A series of ureas was prepared by reacting mono- or di- isocyanates with 3-amino-1H-1,2,4-triazole derivatives. The new carboxamides were investigated as activators of two human (h) carbonic anhydrases (CAs, EC 4.2.
View Article and Find Full Text PDFDiscovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part II).
Bioorg Med Chem Lett
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LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA.
A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile.
View Article and Find Full Text PDFDiscovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part I).
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LGCR SMRPD Chemical Research, Sanofi US, 153-1-122, 153 2nd Ave, Waltham, MA 02451, USA.
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.
View Article and Find Full Text PDFReceptor-specific functional efficacies of alkyl imidazoles as dual histamine H3/H4 receptor ligands.
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Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, ZAFES/NeFF/OSF/CMP, Frankfurt/Main, Germany.
Histamine H(3) and H(4) receptors are highly related G protein-coupled receptors. Preclinical and clinical data strongly suggest the potential therapeutic application of selectively acting histamine H(4) receptor ligands to inflammatory conditions but also hint at a certain interference of the two receptors in diseases attended with itch and pain. The aim of this investigation was to identify dual acting ligands as pharmacological tools.
View Article and Find Full Text PDFUreas with histamine H3-antagonist receptor activity--a new scaffold discovered by lead-hopping from cinnamic acid amides.
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Medicinal Chemistry Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
A group of tri and tetrasubstituted urea derivatives have been found to be hH(3)-antagonists. The most potent compounds were found in the class of (piperazine-1-yl)-(piperidine-1-yl)-methanones which in addition showed negligible hERG inhibition.
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