A Potent, Long-Acting, Orally Active (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: Novel Muscarinic M(3) Receptor Antagonist With High Selectivity for M(3) Over M(2) Receptors

J Med Chem. 2000 Dec 28;43(26):5017-29. doi: 10.1021/jm0003135.

Abstract

A novel series of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M(3) receptor selective antagonist 1, to develop a potent, long-acting, orally active M(3) antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M(3) over M(2) receptors in comparison with the corresponding cyclopentylphenylacetic acid group. However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1-(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M(3) receptors (K(i) = 2.8 nM) over M(2) receptors (K(i) = 530 nM) in a human binding assay and good in vitro metabolic stability in dog and human hepatic microsomes was identified. This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced bronchoconstriction in dogs, and may be useful in clinical situations in which M(3) over M(2) selectivity is desirable.

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / chemistry
  • Acetamides / metabolism
  • Acetamides / pharmacology
  • Acetanilides*
  • Administration, Oral
  • Animals
  • Bronchoconstriction / drug effects
  • Bronchodilator Agents / chemical synthesis*
  • Bronchodilator Agents / chemistry
  • Bronchodilator Agents / metabolism
  • Bronchodilator Agents / pharmacology
  • CHO Cells
  • Cricetinae
  • Dogs
  • Drug Stability
  • Humans
  • Microsomes, Liver / metabolism
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / chemistry
  • Muscarinic Antagonists / metabolism
  • Muscarinic Antagonists / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism
  • Structure-Activity Relationship
  • Transfection

Substances

  • Acetamides
  • Acetanilides
  • Bronchodilator Agents
  • Muscarinic Antagonists
  • N-(1-(6-aminopyridin-2-ylmethyl)piperidin-4-yl)-2-(3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetamide
  • Piperidines
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic