Improving the oral efficacy of CNS drug candidates: discovery of highly orally efficacious piperidinyl piperidine M2 muscarinic receptor antagonists.

In search of a backup M(2) muscarinic receptor antagonist to the previously reported compound 1, we discovered compound (+)-14, which showed superior oral efficacy in animal models. The improvement of oral efficacy was achieved by modulating both the molecular weight and lipophilicity of the lead compounds.

The use of in vitro metabolic stability for rapid selection of compounds in early discovery based on their expected hepatic extraction ratios.

Purpose: The in vivo hepatic extraction ratio of cynomolgus monkeys was correlated with the corresponding in vitro extraction ratios that were determined in monkey microsomal incubations.

Method: For compounds that are eliminated mainly through liver phase I metabolism, the extraction ratio calculated from liver microsomal stability studies should correlate with their in vivo hepatic extraction ratios and also with their oral bioavailability in monkey. We used both well-stirred and parallel tube models of intrinsic clearance for the correlation.

Enhancement of pharmacokinetic properties and in vivo efficacy of benzylidene ketal M(2) muscarinic receptor antagonists via benzamide modification.

We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.