Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, United States.
Janssen Research and Development, 3210 Merryfield Row, San Diego, California 92121, United States.
J Med Chem. 2020 Mar 26;63(6):2915-2929. doi: 10.1021/acs.jmedchem.9b01439. Epub 2020 Mar 16.
To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.
为了鉴定选择性靶向胃肠道组织且全身暴露有限的 Janus 激酶（JAK）抑制剂，我们合成了一系列具有不同物理性质的咪唑并吡咯吡啶类化合物，并对其进行了评估。我们发现了一些具有低内在通透性的化合物，并确定了一组化合物的通透性与理化性质（clogP 和 tPSA）之间的相关性。这种低内在通透性导致化合物在以 25mg/kg 的剂量经口给药后在小鼠中表现出高结直肠暴露和低全身暴露。在一个小鼠 PK/PD 模型中，口服给予先导化合物 后，在口服剂量后，结肠外植体中的 pSTAT 磷酸化呈剂量依赖性抑制，但全身暴露低，无可测量的全身药效学活性。因此，我们证明了具有低内在通透性的 JAK 抑制剂的实用性，这是一种开发肠道限制、具有药理活性的分子的可行方法，与受全身靶点不良反应限制的全身可用化合物相比，具有潜在优势。
