Structure-Based Design of Active-Site-Directed, Highly Potent, Selective, and Orally Bioavailable Low-Molecular-Weight Protein Tyrosine Phosphatase Inhibitors

Protein tyrosine phosphatases constitute an important
class of
drug targets whose potential has been limited by the paucity of drug-like
small-molecule inhibitors. We recently described a class of active-site-directed,
moderately selective, and potent inhibitors of the low-molecular-weight
protein tyrosine phosphatase (LMW-PTP). Here, we report our extensive
structure-based design and optimization effort that afforded inhibitors
with vastly improved potency and specificity. The leading compound
inhibits LMW-PTP potently and selectively (Ki = 1.2 nM, >8000-fold selectivity). Many compounds exhibit
favorable drug-like properties, such as low molecular weight, weak
cytochrome P450 inhibition, high metabolic stability, moderate to
high cell permeability (Papp > 0.2 nm/s), and moderate to good
oral
bioavailability (% F from 23 to 50% in mice), and
therefore can be used as in vivo chemical probes to further dissect
the complex biological as well as pathophysiological roles of LMW-PTP
and for the development of therapeutics targeting LMW-PTP.

蛋白质酪氨酸磷酸酶构成了一类重要的药物靶点，其潜在价值受限于类似药物的的小分子抑制剂数量稀少。我们近期描述了一类针对活性位点、具有中等选择性且高效的低分子量蛋白质酪氨酸磷酸酶（LMW-PTP）抑制剂。在此，我们报告了我们对基于结构的抑制剂设计及优化的广泛努力，这些努力使得抑制剂的活性和特异性得到了显著提升。其中，领先化合物对LMW-PTP表现出强大的选择性抑制效果（Ki = 1.2 nM，选择性大于8000倍）。许多化合物展现出优良的药物特性，例如低分子量、对细胞色素P450的弱抑制作用、高代谢稳定性、适中的至高细胞通透性（Papp > 0.2 nm/s）以及适中的至良好的口服生物利用度（小鼠中的%F从23%至50%），因此可用作体内化学探针，以进一步解析LMW-PTP复杂的生物学及病理生理学作用，并为针对LMW-PTP的治疗药物开发提供支持。