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

[Image: see text] 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.