生物利用度
化学
药代动力学
基础(医学)
胰岛素
药理学
蛋白质水解
甘精胰岛素
赖氨酸
内科学
生物化学
氨基酸
医学
酶
低血糖
作者
Thomas Kjeldsen,František Hubálek,Tina M. Tagmose,Lone Pridal,Hanne H. F. Refsgaard,Trine Porsgaard,Sanne Gram-Nielsen,Lars Hovgaard,Henrik Valore,Martin Münzel,Claudia U. Hjørringgaard,Claus Jeppesen,Valentina Manfè,Thomas Hoeg‐Jensen,Svend Ludvigsen,Peter Kresten Nielsen,Inger Lautrup-Larsen,Carsten E. Stidsen,Erik Max Wulff,Patrick Garibay,János T. Kodra,Erica Nishimura,Peter Madsen
标识
DOI:10.1021/acs.jmedchem.0c01576
摘要
Recently, the first basal oral insulin (OI338) was shown to provide similar treatment outcomes to insulin glargine in a phase 2a clinical trial. Here, we report the engineering of a novel class of basal oral insulin analogues of which OI338, 10, in this publication, was successfully tested in the phase 2a clinical trial. We found that the introduction of two insulin substitutions, A14E and B25H, was needed to provide increased stability toward proteolysis. Ultralong pharmacokinetic profiles were obtained by attaching an albumin-binding side chain derived from octadecanedioic (C18) or icosanedioic acid (C20) to the lysine in position B29. Crucial for obtaining the ultralong PK profile was also a significant reduction of insulin receptor affinity. Oral bioavailability in dogs indicated that C18-based analogues were superior to C20-based analogues. These studies led to the identification of the two clinical candidates OI338 and OI320 (10 and 24, respectively).
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