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2004
Imidazole derivatives
R 0190
Synthesis and Biological Evaluation of Imidazole-Based Small Molecule Antagoof the Melanocortin 4 Receptor (MC4-R). — An initial amidine-based small
46- 120 nists
molecule antagonist is modified by replacing the amidine moiety with imidazole ring
systems. The synthesis of imidazoles (VII) involves alkylation of (I), coupling of intermediates (III) with amino alcohols (IV), and cyclization of hydroxy amides (V) via
chlorination, followed by reaction with methylamine (VI) and NaOH. Finally, the imidazoline intermediates are oxidized to imidazoles (VII). Fused imidazoles, e.g. (X),
are obtained by reaction of nitrile intermediates with (aminomethyl)pyrrolidine or
piperidine in the presence of H2S. The resulting imidazolines are oxidized to the corresponding imidazoles. Compounds (VII) display sub-micromolar binding affinity and
potently antagonize the MC4-R. Dimethyl derivative (VIIb) is the most potent antagonist identified. Representative imidazole (X) shows improved pharmacokinetics and
oral exposure compared to the initial amidine lead. — (MARSILJE*, T. H.; et al.;
Bioorg. Med. Chem. Lett. 14 (2004) 14, 3721-3725; Dep. Med. Chem., Millenium
Pharm., Inc., Cambridge, MA 02139, USA; Eng.) — H. Hoennerscheid
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