胃肠道
肠易激综合征
生物利用度
药理学
吸收(声学)
运输机
便秘
肾
效力
钠氢反转运蛋白
食品药品监督管理局
化学
医学
钠
胃肠病学
内科学
生物化学
体外
有机化学
物理
基因
声学
作者
J. W. Jacobs,Michael R. Leadbetter,Noah Bell,Samantha Koo-McCoy,Christopher W. Carreras,Liyu He,Jill Kohler,Kenji Kozuka,Eric D. Labonté,Marc Navre,Andrew Spencer,Dominique Charmot
标识
DOI:10.1021/acsmedchemlett.2c00037
摘要
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.
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