We started our investigation by evaluating

We started our investigation by evaluating the impact of changes to the piperidine moiety of (). As demonstrated with morpholine and piperazine , attenuation of nitrogen basicity resulted in complete loss of activity, suggesting that a basic heterocyclic nitrogen is important for potent inhibition. Changes to the size of the piperidine ring of gave mixed results. Expansion from a six- to a seven-membered ring ( and , respectively) was favored while conversion of to the corresponding azabicyclo[3.2.2]nonane resulted in a 10-fold loss of potency. Ring truncation (diethylamine ) or contraction (pyrrolidine ) also decreased in vitro glycine uptake inhibition by approximately 10-fold. These results suggest that there is a narrow SAR for the heterocycle moiety of the phenethyl diamine scaffold, and only certain ring sizes and substitutions (e.g., ) maintain or improve potency. To determine what impact modifications might have on both potency and aqueous solubility, we examined alkyl, benzyl and alternative heterocyclic sulfonamides for comparison with simple phenyl analog (). Initial data suggested that an aromatic moiety is required for activity. For example, while both compounds showed marked improvement in solubility relative to their aromatic counterparts, ethyl () and cyclopropyl () sulfonamides were inactive. Several results indicated that large lipophilic aromatic groups are well tolerated. Thus, while only weak activity was observed for benzyl sulfonamide , bis-chlorination () improved potency by 10-fold. Similarly, potency was retained in going from to quinoline . Thiophene , with a large bromo substituent, was the most potent phenyl sulfonamide surrogate tested. In contrast, an attempt to increase solubility by conversion of the phenyl sulfonamide of to a more polar pyridine analog () completely eliminated activity. We concluded from the data of that phenyl sulfonamides offer the best combination of potency and solubility, prompting us to aggressively investigate the scope of sulfonamide phenyl ring synthase (). In general, and -substituted phenyl sulfonamides with large hydrophobic substituents were more active than sulfonamides with alternative substitution patterns or polar substituents. Supporting this hypothesis are -substituted bromo and trifluoromethoxy analogs and , respectively, which are two of the more potent compounds of . In contrast, replacing chlorine with fluorine (e.g., to and to ) improved solubility but reduced potency. Electron withdrawing cyano ( and ) and electron donating methoxy () moieties gave similar results, while sulfone was completely inactive. Hydrophobic substituents at the position () retained only modest activity. Interestingly, compound , with polar and non-polar moieties at the and positions, respectively, represents a successful increase in solubility while maintaining activity at GlyT1 comparable to . We used 4-trifluoromethyl sulfonamide as a platform to scope the impact of substitution of the phenyl ring of the 2-(azepan-1-yl)-2-phenylethanamine scaffold (). substitution was only briefly explored and was not well-tolerated (data not shown). Electron withdrawing groups at the position were weakly active. Of sulfones and sulfonamides and –, only propylsulfone retained any significant potency. Solubility was also low, which was likely due to the hydrophobic nature of the propyl side chain. Sulfonamide was weakly active but approximately fourfold more potent than less lipophilic , again suggesting that lipophilic electron withdrawing groups at the position are favored. substitution had the greatest impact on in vitro potency, particularly when that substituent was a methoxy group ( and ). Not only was there more than a two- to fivefold increase in uptake inhibition, but a significant increase in solubility was also observed for compared to (). In contrast, an electron withdrawing group at the position () decreased potency by two orders of magnitude. With regards to other alkoxy substituted analogs, dioxolane was potent but less active than , and had little to no aqueous solubility. Bis-substituted , which could potentially capitalize on increased binding interactions via rotation of the phenyl ring, was weakly active.