Privileged Structure-based Discovery of Novel 2-Iminothiazoles as Protein Tyrosine Phosphatase 1B Inhibitors

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a wellestablished metabolic regulator and a member of PTP superfamily that catalyzes protein tyrosine dephosphorylation. Many scientific evidences have shown that PTP1B plays a broad role in the regulation of body metabolism, particularly in cancer development.1-3 In the insulin signaling pathway, PTP1B can be involved in dephosphorylation of activated insulin receptor (IR) or insulin receptor substrates (IRS). PTP1B can also bind and dephosphorylate JAK2, which activates STAT3 responsible for downstream functions such as food uptake and energy homeostasis in the leptin pathway. Elevated leptin sensitivity by activated or phosphorylated JAK2 in the PTP1B −/− mice is related to increased energy expenditure, which eventually results in homeostatic regulation of the blood glucose level and body weight. 4An effective control of the phosphatase may provide a useful tool in treatment of diseases such as type 2 diabetes and obesity. However, there is no reported PTP1B inhibitor that has passed through the sequence of clinical tests for treatment of the diseases, although many inhibitors showed potency in vitro assays. In general, mimicking phosphotyrosine has been the starting point of development of active site-directed PTPase inhibitors.5 However, the majority of the active site directed PTP1B inhibitors have shown a low level of cellular uptake because they usually contain the highly charged moieties such as phosphate and carboxylic acid. Recently, potent PTP1B inhibitors were obtained from high-throughput screening of chemical libraries. Among them, further structurally optimized Ertiprotafib was submitted to a clinical trial but was discontinued in the second phase (Figure 1). 6,7In this regard, our group made much effort to find out new chemical scaffolds with inhibitory activities against PTP1B without mimicking phosphotyrosine. In search of new hit compounds for drug discovery, utilizing chemical library based on privileged structures gives some benefits in terms of proved drug-like properties such as inherent low toxicity, good pharmacokinetic profiles, and easiness of synthesis. 8,9Therefore, structurally diversified chemical set was selected from our proprietary privileged structure-based chemical library, which was designed and constructed for drug discovery. Herein, we communicate discovery of novel 2-iminothiazole compounds for PTP1B as a potential anti-diabetic.Initially, 182 compounds were screened for PTB1B inhibitory activities at 100 μM using fluorescence polarization (FP)-based PTP1B assays to give 20 compounds which showed over 50% inhibition. Then, selected compounds were screened again at 20 μM to give two hit compounds with 22% and 99% inhibitory activities, respectively. These two compounds share common structure, N-cyclohexyl-2-(3-methyl-2-(phenylimino)-2,3-dihydrothiazol-4-yl)acetamide (Figure 2).With initial hit compounds in hand, we designed new chemical library focused on 2-aryliminothiazole moiety. Synthesis of the library was carried out followi...