ABSTRACT
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.
Subject(s)
Autoreceptors/antagonists & inhibitors , Central Nervous System Agents/chemical synthesis , Muscarinic Antagonists/chemical synthesis , Piperidines/chemical synthesis , Receptors, Muscarinic/drug effects , Acetylcholine/metabolism , Administration, Oral , Animals , Avoidance Learning/drug effects , Central Nervous System Agents/chemistry , Central Nervous System Agents/pharmacology , Corpus Striatum/metabolism , Humans , In Vitro Techniques , Microdialysis , Molecular Conformation , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Rats , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
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. We also calculated extraction ratios for compounds within a given therapeutic area from fraction absorbed values that were estimated from the Caco-2 absorption model. RESULT: The present data show that in vitro extraction ratios in monkey microsomes are predictive of the in vivo hepatic extraction ratios in monkeys. All compounds with high extraction ratio (>70%) in vivo were successfully classified as high-extraction-ratio compounds based on the in vitro monkey microsomal stability data. From the results of this study, it appears that the parallel tube model provided a slightly better classification than the well-stirred model. CONCULUSIONS: The present method appears to be a valuable tool to rapidly screen and prioritize compounds with respect to liver first-pass metabolism in monkeys at an early phase of drug discovery.
Subject(s)
Microsomes, Liver/metabolism , Pharmaceutical Preparations/metabolism , Technology, Pharmaceutical/methods , Animals , Caco-2 Cells , Enzyme Stability/drug effects , Enzyme Stability/physiology , Forecasting , Humans , Macaca fascicularis , Metabolic Clearance Rate/drug effects , Metabolic Clearance Rate/physiology , Microsomes, Liver/drug effectsABSTRACT
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.