Analogs of M4 selective synthetic muscarinic receptor antagonists:: Synthesis, binding and pharmacokinetic properties

Recently, highly selective M-4 muscarinic receptor antagonists (e.g., PD 0320115) have been synthesized and pharmacologically characterized. One compound, PD 0298029 which was selected for in vivo testing, had low bioavailability (rat similar to5 %) and proved to be susceptible to fast metabolism resulting in high clearance (rat: 60 mL / min / kg). In an effort to improve stability, we focused on the replacement of the hemi-aminal structure in PD 0298029, a moiety which may cause this instability. Therefore, the oxygen of the hemi-aminal was exchanged with a carbon. The in vivo pharmacokinetic data clearly indicated that this change yielded a more stable compound (rat: clearance: 8 mL / min / kg) with improved bioavailability (similar to30 %). However, this substitution significantly decreased the binding affinity at M-4 receptors. Another potential unstable moiety in the molecule is the ester group in PD 0298029 that may undergo enzymatic cleavage. Replacing this ester group with an oxadiazole moiety was synthesized. While M-4 affinity was reduced, bioavailability was increased higher (rat: similar to44 %) but high clearance (rat: 78 mL / min / kg) was retained.