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  • Generally replacement of the aryl group

    2022-01-17

    Generally, replacement of the aryl group was well tolerated, with tetrahydropyran () and hydroxyl () functionality providing potency equivalent to and . These substitutions had no effect on selectivity versus GlyT2 and taurine transporter (TauT)—no activity was observed at micromolar concentrations. This level of selectivity (>30,000-fold) is notable among non-sarcosine derived GlyT1 inhibitors. Despite the variety of structures incorporated at the piperidine C4 position and the removal of likely sites of 4-P-PDOT (aromatic oxidation and -oxide formation), compounds in exhibited uniformly poor pharmacokinetic properties (dog Cl>15mL/min/kg, <2h). Evaluation of propylsulfonamide modifications was therefore undertaken; a focused sulfonamide library was prepared according to and results are shown in . Metabolite profiling of indicated that oxidation occurs on the propyl chain, and potential metabolite lost 20-fold in potency. The corresponding fluoride (), while only 2× less potent than , demonstrated poor pharmacokinetics. Alkyl sulfonamides (–) were 10- to 50-fold less potent than , with the truncation and extension of the straight alkyl chain by even a single methylene unit having a significant negative effect ( and , respectively). Sulfamide () and trifluorinated alkyl chains ( and ) were poorly tolerated. Although the truncated alkyl sulfonamides (, , and ) lose potency versus and , they constitute a breakthrough in terms of pharmacokinetic properties (). These compounds exhibit low clearance (<2mL/min/kg) and long half lives (>7.5h) in dogs. The data cited in were generated in a series of dog iv cassette experiments, which was an attractive strategy due to the number of compounds in the library for which pharmacokinetic evaluation was desired. Although there are myriad potential complications associated with dosing in cassette format, within this structural series we noted excellent agreement between iv clearance values determined via cassette and single dose experiments. This strong correlation led to a high degree of confidence in these data, and cassettes were followed with single dose experiments evaluating promising compounds. Based on the dramatic improvement in dog clearance afforded by the shortened alkyl sulfonamides, efforts were focused on enhancing potency with these groups in place. Previous experience gained during the development of suggested that incorporation of a chiral () methyl group alpha to the amide nitrogen could confer increases in potency up to 10-fold. The methylated analogue of was therefore prepared according to . Following incorporation of the 2-pyridyl group via a nucleophilic aromatic substitution reaction, the methyl group was installed through Grignard addition (MeMgBr, 25°C) and reduction (NaBH) of the resulting imine. Following resolution using chiral chromatography, acylation of the amine, piperidine -Boc deprotection, and sulfonamide formation provided optically pure . Gratifyingly, exhibited improved GlyT1 potency (11nM) while maintaining complete selectivity versus GlyT2 and TauT; this analogue was not a substrate for human or rat P-glycoprotein (PgP) and displayed excellent passive permeability (37×10cm/s). Moreover, retained a favorable dog pharmacokinetic profile (see and ). Data contained in are derived from a dog iv cassette experiment and illustrate the utility of the approach. Simple visual inspection indicates the comparative stability of and (vide infra) versus , and while iv clearance values were calculated, in general only a rank order of stabilities for compounds in cassettes was generated. Based on this order, compounds were prioritized for evaluation in single compound pharmacokinetic studies from which quantitative parameters were derived (). As noted previously, within this series excellent agreement of cassette and single-compound clearance rates was found. Compound was evaluated in a rat in vivo transporter occupancy assay via oral dosing using the previously described protocol. A plasma Occ of 150nM was measured, and this analogue represents the achievement of the desired profile with respect to in vitro potency and selectivity, pharmacokinetics, and in vivo occupancy.