Discovery of Tenapanor: A First-in-Class Minimally Systemic Inhibitor of Intestinal Na+/H+ Exchanger Isoform 3.

We present herein the design, synthesis, and optimization of gut-restricted inhibitors of Na+/H+ exchanger isoform 3 (NHE3). NHE3 is predominantly expressed in the kidney and gastrointestinal tract where it acts as the major absorptive sodium transporter. We desired minimally systemic agents that would block sodium absorption in the gastrointestinal tract but avoid exposure in the kidney. Starting with a relatively low-potency highly bioavailable hit compound (1), potent and minimally absorbed NHE3 inhibitors were designed, culminating with the discovery of tenapanor (28). Tenapanor has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of irritable bowel syndrome with constipation in adults.

Gastrointestinal Inhibition of Sodium-Hydrogen Exchanger 3 Reduces Phosphorus Absorption and Protects against Vascular Calcification in CKD.

In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodium-hydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [(33)P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders.

Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans.

The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. Tenapanor is an inhibitor of the sodium-proton (Na(+)/H(+)) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. When administered orally to rats, tenapanor acted exclusively in the gastrointestinal tract to inhibit sodium uptake. We showed that the systemic availability of tenapanor was negligible through plasma pharmacokinetic studies, as well as autoradiography and mass balance studies performed with (14)C-tenapanor. In humans, tenapanor reduced urinary sodium excretion by 20 to 50 mmol/day and led to an increase of similar magnitude in stool sodium. In salt-fed nephrectomized rats exhibiting hypervolemia, cardiac hypertrophy, and arterial stiffening, tenapanor reduced extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in a dose-dependent fashion. We observed these effects whether tenapanor was administered prophylactically or after disease was established. In addition, the combination of tenapanor and the blood pressure medication enalapril improved cardiac diastolic dysfunction and arterial pulse wave velocity relative to enalapril monotherapy in this animal model. Tenapanor prevented increases in glomerular area and urinary KIM-1, a marker of renal injury. The results suggest that therapeutic alteration of sodium transport in the gastrointestinal tract instead of the kidney--the target of current drugs--could lead to improved sodium management in renal disease.

Hydrophobic vancomycin derivatives with improved ADME properties: discovery of telavancin (TD-6424).

Novel derivatives of N-decylaminoethylvancomycin (2), containing appended hydrophilic groups were synthesized and their antibacterial activity and ADME properties were evaluated. The compounds were prepared by reacting amines with the C-terminus (C-) of 2 using PyBOP mediated amide formation, or with the resorcinol-like (R-) position of 2 using a Mannich aminomethylation reaction. These analogs retained the antibacterial activity of 2 against methicillin-resistant staphylococci and vancomycin-resistant enterococci. Compounds with a negatively charged auxiliary group also exhibited improved ADME properties relative to 2. In particular, R-phosphonomethylaminomethyl derivative 21 displayed good in vitro antibacterial activity, high urinary recovery and low distribution to liver and kidney tissues. Based on these results, 21 was advanced into development as TD-6424, and is currently in human clinical trials. The generic name telavancin has recently been approved for compound 21.