To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).
[Show abstract][Hide abstract] ABSTRACT: 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)<2 nM (M(3)), M(1)/M(3)>700-fold, M(2)/M(3)>180-fold], which have a more rigid structure than 1.
No preview · Article · Jan 2003 · Bioorganic & Medicinal Chemistry Letters
[Show abstract][Hide abstract] ABSTRACT: [309964-23-6] C12H14O5 (MW 238.24) InChI = 1S/C12H14O5/c1-16-11-7-10(5-4-9(11)8-13)17-6-2-3-12(14)15/h4-5,7-8H,2-3,6H2,1H3,(H,14,15)InChIKey = RHQAFYIBBWZTOI-UHFFFAOYSA-N(reagent is used as an acid labile linker for solid phase synthesis)readily soluble in water at pH 7 and above, sparingly soluble at pH 4 and below. Soluble in organic solvents.Form Supplied in: available from AstaTech, Inc., Philadelphia, PA; Atlantic Scientific Co., Inc., Boonton, NJ; and Tyger Scientific Inc., Ewing, NJ.
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