前药
亲脂性
药代动力学
吸收(声学)
化学
生物制药
体内
药理学
药品
溶解度
组合化学
有机化学
材料科学
生物化学
医学
生物技术
复合材料
生物
遗传学
作者
Rebecca Nofsinger,S.-D. Clas,Rosa I. Sanchez,Abbas M. Walji,Kimberly Manser,Becky Nissley,Jaume Balsells,A. M Nair,Qun Dang,David Jonathan Bennett,Michael Hafey,Junying Wang,John Higgins,Allen C. Templeton,Paul J. Coleman,Jay A. Grobler,Ronald L. Smith,Yunhui Wu
摘要
Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption.
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