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Engineering of Orally Available, Ultralong-Acting Insulin Analogues: Discovery of OI338 and OI320
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-28 , DOI: 10.1021/acs.jmedchem.0c01576 Thomas B. Kjeldsen 1 , František Hubálek 1 , Tina M. Tagmose 1 , Lone Pridal 2 , Hanne H. F. Refsgaard 2 , Trine Porsgaard 2 , Sanne Gram-Nielsen 2 , Lars Hovgaard 1 , Henrik Valore 3 , Martin Münzel 1 , Claudia U. Hjørringgaard 1 , Claus Bekker Jeppesen 2 , Valentina Manfè 2 , Thomas Hoeg-Jensen 1 , Svend Ludvigsen 1 , Peter Kresten Nielsen 1 , Inger Lautrup-Larsen 1 , Carsten E. Stidsen 2 , Erik M. Wulff 2 , Patrick W. Garibay 1 , János T. Kodra 1 , Erica Nishimura 2 , Peter Madsen 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-28 , DOI: 10.1021/acs.jmedchem.0c01576 Thomas B. Kjeldsen 1 , František Hubálek 1 , Tina M. Tagmose 1 , Lone Pridal 2 , Hanne H. F. Refsgaard 2 , Trine Porsgaard 2 , Sanne Gram-Nielsen 2 , Lars Hovgaard 1 , Henrik Valore 3 , Martin Münzel 1 , Claudia U. Hjørringgaard 1 , Claus Bekker Jeppesen 2 , Valentina Manfè 2 , Thomas Hoeg-Jensen 1 , Svend Ludvigsen 1 , Peter Kresten Nielsen 1 , Inger Lautrup-Larsen 1 , Carsten E. Stidsen 2 , Erik M. Wulff 2 , Patrick W. Garibay 1 , János T. Kodra 1 , Erica Nishimura 2 , Peter Madsen 1
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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).
中文翻译：
口服超长效胰岛素类似物的工程设计：发现OI338和OI320
最近，在2a期临床试验中，显示出第一种基础口服胰岛素（OI338）可提供与甘精胰岛素相似的治疗效果。在这里，我们报道了一类新的基础口服胰岛素类似物的工程，其中OI338，10本出版物中的，已在2a期临床试验中成功测试。我们发现需要引入两个胰岛素替代品A14E和B25H，以增加对蛋白水解的稳定性。通过将源自十八烷二酸（C18）或二十烷二酸（C20）的白蛋白结合侧链连接到位置B29的赖氨酸，可获得超长的药物动力学曲线。获得超长PK曲线的关键还在于胰岛素受体亲和力的显着降低。狗的口服生物利用度表明，基于C18的类似物优于基于C20的类似物。这些研究导致鉴定出两个临床候选药物OI338和OI320（分别为10和24）。
更新日期：2021-01-14
中文翻译：
口服超长效胰岛素类似物的工程设计：发现OI338和OI320
最近，在2a期临床试验中，显示出第一种基础口服胰岛素（OI338）可提供与甘精胰岛素相似的治疗效果。在这里，我们报道了一类新的基础口服胰岛素类似物的工程，其中OI338，10本出版物中的，已在2a期临床试验中成功测试。我们发现需要引入两个胰岛素替代品A14E和B25H，以增加对蛋白水解的稳定性。通过将源自十八烷二酸（C18）或二十烷二酸（C20）的白蛋白结合侧链连接到位置B29的赖氨酸，可获得超长的药物动力学曲线。获得超长PK曲线的关键还在于胰岛素受体亲和力的显着降低。狗的口服生物利用度表明，基于C18的类似物优于基于C20的类似物。这些研究导致鉴定出两个临床候选药物OI338和OI320（分别为10和24）。
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