Metabolic Stabilization of Benzylidene Ketal M(2) Muscarinic Receptor Antagonists via Halonaphthoic Acid Substitution

Bioorg Med Chem Lett. 2001 Sep 3;11(17):2311-4. doi: 10.1016/s0960-894x(01)00435-8.

Abstract

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.

MeSH terms

  • Acetylcholine / analysis
  • Acetylcholine / metabolism
  • Administration, Oral
  • Animals
  • Area Under Curve
  • Benzylidene Compounds / chemistry*
  • Benzylidene Compounds / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Dioxoles / chemistry*
  • Dioxoles / pharmacology*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Humans
  • Macaca fascicularis
  • Microdialysis
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Muscarinic Antagonists / blood
  • Muscarinic Antagonists / chemistry*
  • Muscarinic Antagonists / pharmacology*
  • Rats
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / drug effects*
  • Structure-Activity Relationship
  • Sulfones / chemistry*
  • Sulfones / pharmacology*

Substances

  • 1-((3,4-methylenedioxyphenyl)sulfonylphenyl)-1-(1-(1-(n-propylsulfonyl)morpholin-4-yl)morpholin-4-yl)dioxole
  • 1-((4-methoxyphenyl)sulfonylphenyl)-1(1-(1-(1-naphthylcarbonyl)morpholin-4-yl)morpholin-4-yl)dioxole
  • 1-((4-methoxyphenyl)sulfonylphenyl)-1-(1-(1-(4-fluoro-1-naphthylcarbonyl)morpholin-4-yl)morpholin-4-yl)dioxole
  • Benzylidene Compounds
  • Dioxoles
  • Muscarinic Antagonists
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic
  • Sulfones
  • Cytochrome P-450 Enzyme System
  • Acetylcholine