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Objective: This pilot study aimed to develop a liquid formulation of tenapanor and evaluate taste and palatability with different sweetener and flavor combinations., Significance: Tenapanor is a first-in-class, minimally absorbed, small molecule inhibitor of intestinal sodium/hydrogen exchanger 3, indicated (as tablets) to treat adults with constipation-predominant irritable bowel syndrome. It is also approved as add-on therapy to reduce serum phosphorus in adults with chronic kidney disease on dialysis who are intolerant of, or unacceptably responsive to, any dose of phosphate binder therapy. Since many patients have difficulty swallowing pills and pediatric studies are underway, a liquid formulation was developed, and taste profiles were evaluated for overall acceptability., Methods: Formulation of liquid tenapanor targeted a concentration of 5 mg/mL, for a dosing range of 1-50 mg twice daily. Improvements in solubility and stability of tenapanor in water were investigated with the use of buffers, cosolvents, and preservatives. Seven liquid formulations with different sweetener/flavor combinations were assessed for taste and palatability by healthy adult participants using the sip-and-spit method in a randomized design., Results: An aqueous solution of tenapanor (5 mg/mL), pH 3.4, with 0.05 % (w/v) benzoic acid, was stable at 2-8 °C for 12 months. The formulation with sucralose and raspberry flavor had the greatest improvement in overall acceptability and taste when compared to the reference solution without sweeteners or flavors., Conclusions: A suitable liquid formulation was identified for progression to patient studies.

The selectivity of an enzyme inhibitor is a key determinant of its usefulness as a tool compound or its safety as a drug. Yet selectivity is never assessed comprehensively in the early stages of the drug discovery process, and only rarely in the later stages, because technical limitations prohibit doing otherwise. Here, we report EnPlex, an efficient, high-throughput method for simultaneously assessing inhibitor potency and specificity, and pilot its application to 96 serine hydrolases. EnPlex analysis of widely used serine hydrolase inhibitors revealed numerous previously unrecognized off-target interactions, some of which may help to explain previously confounding adverse effects. In addition, EnPlex screening of a hydrolase-directed library of boronic acid- and nitrile-containing compounds provided structure-activity relationships in both potency and selectivity dimensions from which lead candidates could be more effectively prioritized. Follow-up of a series of dipeptidyl peptidase 4 inhibitors showed that EnPlex indeed predicted efficacy and safety in animal models. These results demonstrate the feasibility and value of high-throughput, superfamily-wide selectivity profiling and suggest that such profiling can be incorporated into the earliest stages of drug discovery.