Metabolic stabilization of benzylidene ketal M2 muscarinic receptor antagonists via halonaphthoic acid substitution

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.