- TGR5 AGONISTS
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TGR5 agonists of structural formula VIII(Q), wherein X, R1, R2, and R5 are defined in the specification, pharmaceutically acceptable salts thereof, compositions thereof, and use of the compounds and compositions for treating diseases. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases.
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Page/Page column 184
(2011/06/26)
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- Quinazoline derivatives useful in cancer treatment
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The present invention provides compounds of Formula I (wherein R1, R2, R3, L, and X are as defined herein). [image] or a pharmaceutically acceptable salt, solvate or ester thereof. The present invention also provides compositions comprising these compound
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Page/Page column 220
(2010/11/25)
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- Design and synthesis of novel sulfonamide-containing bradykinin hB 2 receptor antagonists. 2. Synthesis and structure-activity relationships of α,α-cycloalkylglycine sulfonamides
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Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.
- Fattori, Daniela,Rossi, Cristina,Fincham, Christopher I.,Caciagli, Valerio,Catrambone, Fernando,D'Andrea, Piero,Felicetti, Patrizia,Gensini, Martina,Marastoni, Elena,Nannicini, Rossano,Paris, Marielle,Terracciano, Rosa,Bressan, Alessandro,Giuliani, Sandro,Maggi, Carlo A.,Meini, Stefania,Valenti, Claudio,Quartara, Laura
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p. 550 - 565
(2007/10/03)
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- Effects of chain length and N-methylation on a cation-π interaction in a β-hairpin peptide
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The effects of N-methylation and chain length on a cation-π interaction have been investigated within the context of a β-hairpin peptide. Significant enhancement of the interaction and structural stabilization of the hairpin have been observed upon Lys methylation. Thermodynamic analysis indicates an increased entropie driving orce for folding upon methylation of Lys residues. Comparison of lysine to analogues ornithine (Orn) and iaminobutyric acid (Dab) indicates that lysine provides the strongest cation-π interaction and also provides the most stable β-hairpin due to a combination of side chain-side chain interactions and β-sheet propensities. These studies have significance for the recognition of methylated lysine in histone proteins.
- Hughes, Robert M.,Benshoff, Matthew L.,Waters, Marcey L.
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p. 5753 - 5764
(2008/02/13)
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