Muscarinic M(3) Receptor Antagonists With (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxyphenylacetamide Structures. Part 2

Bioorg Med Chem Lett. 2003 Jul 7;13(13):2167-72. doi: 10.1016/s0960-894x(03)00350-0.


Optimization of the amine part of our original muscarinic M(3) receptor antagonist 1 was performed to identify M(3) receptor antagonists that are superior to 1. Compounds carrying a variety of diamine moieties without hydrophobic substituent on the nitrogen atom were screened against the binding affinity for the M(3) receptor and the selectivity for M(3) over the M(1) and M(2) receptors. This process led to a 4-aminopiperidinamide (2l) with a K(i) value of 5.1 nM and with a selectivity of the M(3) receptor that was 46-fold greater than that of the M(2) receptor. Further derivatization of 2l by inserting a spacer group or by incorporating alkyl group(s) into the amine part resulted in the identification of an 4-(aminoethyl)piperidinamide 2l-b with a K(i) value of 3.7 nM for the M(3) receptor and a selectivity for the M(3) receptor that was 170-fold greater than that of the M(2) receptor.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / pharmacokinetics
  • Acetamides / pharmacology*
  • Animals
  • Area Under Curve
  • CHO Cells
  • Cricetinae
  • Cyclopentanes / chemical synthesis*
  • Cyclopentanes / pharmacokinetics
  • Cyclopentanes / pharmacology*
  • Dogs
  • Humans
  • Indicators and Reagents
  • Kinetics
  • Microsomes, Liver / metabolism
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / pharmacokinetics
  • Muscarinic Antagonists / pharmacology*
  • Rats
  • Receptor, Muscarinic M3 / drug effects*
  • Structure-Activity Relationship
  • Transfection


  • (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxyphenylacetamide
  • Acetamides
  • Cyclopentanes
  • Indicators and Reagents
  • Muscarinic Antagonists
  • Receptor, Muscarinic M3