Identification of novel muscarinic M(3) selective antagonists with a conformationally restricted Hyp-Pro spacer

The identification of potent and selective muscarinic M(3) antagonists that are based on the recently discovered triphenylpropioamide derivative, 1, and have a unique amino acid spacer group is described. The introduction of a hydroxyproline-proline group to the spacer site and the use of a propyl o...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2003-01, Vol.13 (1), p.57-60
Main Authors: Sagara, Yufu, Kimura, Toshifumi, Fujikawa, Toru, Noguchi, Kazuhito, Ohtake, Norikazu
Format: Article
Language:English
Subjects:
Amides
Combinatorial Chemistry Techniques
Drug Evaluation, Preclinical
Humans
Hydroxyproline
Molecular Conformation
Muscarinic Antagonists - chemistry
Muscarinic Antagonists - metabolism
Protein Binding
Receptor, Muscarinic M3
Receptors, Muscarinic - chemistry
Receptors, Muscarinic - metabolism
Structure-Activity Relationship
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Summary:The identification of potent and selective muscarinic M(3) antagonists that are based on the recently discovered triphenylpropioamide derivative, 1, and have a unique amino acid spacer group is described. The introduction of a hydroxyproline-proline group to the spacer site and the use of a propyl or cyclopropylmethyl group as the piperidine N-substituent led to the discovery of the novel M(3) selective antagonists [8c, 8g; K(i)700-fold, M(2)/M(3)>180-fold], which have a more rigid structure than 1.
ISSN:0960-894X