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  • An alternative approach to improving


    An alternative approach to improving pharmacokinetic profile while retaining high GlyT1 potency was also pursued. Libraries were prepared in which potency enhancing piperidine C4 substituents were combined with clearance lowering truncated alkyl sulfonamides. The result was the discovery of (). Unlike the 4-pyridylpiperidine series, where truncation of the propylsulfonamide to an ethylsulfonamide results in a >10-fold decrease in potency (compare and in ), within the 4-cyclopropylmethylpiperidine series the propyl and ethyl sulfonamides are equipotent (for and GlyT1 IC 30 and 26nM, respectively). In the 4-cyclopropylmethylpiperidine series incorporation of a chiral methyl group did not confer an increase in potency (data not shown). Despite these differences, retains the favorable profile of the 4-pyridylpiperidine series. Compound is not a substrate for human or rat PgP. Like , compound exhibits low clearance when dosed in either iv cassette () or single format (iv and po, ). Compound was suitable for evaluation in the in vivo transporter occupancy assay and has a plasma Occ of 260nM. In conclusion, the pharmacokinetic profile of GlyT1 inhibitors within the 4,4-disubstituted piperidine series has been dramatically improved through modification of the sulfonamide alkyl chain. Accompanying losses in potency could be recovered through the installation of a chiral methyl group alpha to the amide nitrogen and through exchange of the 2-pyridyl group with a cyclopropylmethyl substituent. The improvements include an increase GW788388 in bioavailability which allowed, for the first time, the measurement of in vivo transporter occupancy using oral dosing. Compounds and were identified which occupy GW788388 GlyT1 in vivo at plasma concentrations <300nM. The use of an iterative analogue library approach enabled the optimization of both potency and pharmacokinetic properties despite non-additive SAR. Key to the successful discovery of enhanced inhibitors was the extensive use of cassette dosing in dog pharmacokinetic experiments which, when combined with judicious follow up in single dose experiments, allowed the screening of hundreds of compounds for improved pharmacokinetics. Acknowledgments We are grateful to Audrey Wallace for dog PK experiments and Ken Anderson and Kristi Hoffman for analytical measurements. We thank Carl Homnick for performing chiral separations, Joan Murphy and Charles W. Ross, III, for HRMS measurements, and Nancy Tsou for X-ray crystal analysis of 21.
    The amino acid glycine is a major neurotransmitter in the mammalian CNS with both inhibitory and excitatory actions. It has also been shown to modulate excitatory neurotransmission as obligatory co-agonist with glutamate at NMDA receptors in the pre-frontal cortex. NMDA receptor hypofunction has been implicated in the etiology of schizophrenia and NMDA receptor activation constitutes a potential strategy for the development of novel schizophrenia treatments. Since direct acting NMDA receptor agonists are epileptogenic and excitotoxic, indirect modulation of the NMDA receptor through its co-agonist (glycine) binding site has received considerable attention as a potentially non-toxic approach. Glycine uptake is mediated by two glycine transporters, GlyT1 and GlyT2, which belong to the family of Na/Cl-dependent neurotransmitter transporters. Since NMDA receptors are co-localized with GlyT1, this transporter may be involved in the regulation of extracellular glycine concentrations at NMDA receptors. Modulation of extracellular glycine levels by glycine transporter inhibition therefore constitutes a novel strategy for the treatment of positive and negative symptoms of schizophrenia including its cognitive deficits. shows the structure of several reported GlyT1 inhibitors., , Although these compounds form a structurally heterogeneous group, a sarcosine (-methyl glycine) substructure as in is a known motif. Piperazinyl acetic acids such as are structurally related to sarcosines. Other structural types without a carboxylate group have also been described, for example, , , , and . Herein, we disclose the discovery and SAR studies of a novel class of GlyT1 inhibitors in which the sarcosine group is linked to a substituted biphenyl system via an ethanolamine linker ().