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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Jul 21

PMID 35859876

Authors

Jeffrey W Jacobs

Michael R Leadbetter

Noah Bell

Samantha Koo-McCoy

Christopher W Carreras

Limin He

Jill Kohler

Kenji Kozuka

Eric D Labonte

Marc Navre

Andrew G Spencer

Dominique Charmot

Affiliations

Soon will be listed here.

Abstract

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 (), potent and minimally absorbed NHE3 inhibitors were designed, culminating with the discovery of tenapanor (). Tenapanor has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of irritable bowel syndrome with constipation in adults.

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