Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M 1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M 1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability. Compound 5 showed robust in vivo activities in animal models of cognition enhancement. The combination of high potency, excellent selectivity, and good PK properties makes compounds 4 and 5 valuable tool compounds for investigating and validating potential therapeutic benefits resulting from selective M 1 activation.

ABSTRACT:This study was designed to investigate whether brain unbound concentration (C u,brain ) is a better predictor of dopamine D 2 receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C CSF ), or blood unbound concentration (C u,blood ). The ex vivo D 2 receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The C u,brain was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C u,brain of selected antipsychotic agents is a good predictor of D 2 receptor occupancy in rats. Furthermore, C u,brain seems to provide a better prediction of D 2 receptor occupancy than C CSF or C u,blood for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.

The penetration of drugs into the central nervous system is a composite of both the rate of drug uptake across the blood-brain barrier and the extent of distribution into brain tissue compartments. Clinically, positron emission tomography (PET) is the primary technique for deriving information on drug biodistribution as well as target receptor occupancy. In contrast, rodent models have formed the basis for much of the current understanding of brain penetration within pharmaceutical Drug Discovery. Linking these two areas more effectively would greatly improve the translation of candidate compounds into therapeutic agents. This paper examines two of the major influences on the extent of brain penetration across species, namely plasma protein binding and brain tissue binding. An excellent correlation was noted between unbound brain fractions across species (R(2) > 0.9 rat, pig, and human, n = 21), which is indicative of the high degree of conservation of the central nervous system environment. In vitro estimates of human brain-blood or brain-plasma ratios of marketed central nervous system drugs and PET tracers agree well with in vivo values derived from clinical PET and post-mortem studies. These results suggest that passive diffusion across the blood-brain barrier is an important process for many drugs in humans and highlights the possibility for improved prediction of brain penetration across species.

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