Dual PTP1B/TC-PTP Inhibitors: Biological Evaluation of 3-(Hydroxymethyl)cinnoline-4(1H)-Ones

Abstract

Dual inhibitors of protein phosphotyrosine phosphatase 1B (PTP1B)/T-cell protein phosphotyrosine phosphatase (TC-PTP) based on the 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline scaffold have been identified. Their dual affinity to both enzymes has been thoroughly corroborated by in silico modeling experiments. The compounds have been profiled in vivo for their effects on body weight and food intake in obese rats. Likewise, the effects of the compounds on glucose tolerance, insulin resistance, as well as insulin and leptin levels, have been evaluated. In addition, the effects on PTP1B, TC-PTP, and Src homology region 2 domain-containing phosphatase-1 (SHP1), as well as the insulin and leptin receptors gene expressions, have been assessed. In obese male Wistar rats, a five-day administration of all studied compounds led to a decrease in body weight and food intake, improved glucose tolerance, attenuated hyperinsulinemia, hyperleptinemia and insulin resistance, and also compensatory increased expression of the PTP1B and TC-PTP genes in the liver. The highest activity was demonstrated by 6-Chloro-3-(hydroxymethyl)cinnolin-4(1H)-one (compound 3) and 6-Bromo-3-(hydroxymethyl)cinnolin-4(1H)-one (compound 4) with mixed PTP1B/TC-PTP inhibitory activity. Taken together, these data shed light on the pharmacological implications of PTP1B/TC-PTP dual inhibition, and on the promise of using mixed PTP1B/TC-PTP inhibitors to correct metabolic disorders.

Site-Specifically Modified Peptide Inhibitors of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase with Enhanced Stability and Improved In Vivo Long-Acting Activity

“…However, gaining insights into the functional roles of PTP1B and TC-PTP in cellular signaling, they are both capable of attenuating the insulin and leptin signaling pathways by dephosphorylating their receptor and downstreaming signal molecules. Consequently, the concurrent inhibition of PTP1B and TC-PTP holds the potential to yield synergistic benefits across a range of therapeutic applications, encompassing type 2 diabetes, obesity, and anticancer immunotherapies. ,,,, As illustrated in Table , S2 , S6 , A2–17 , and A2–21 all exhibited excellent PTP1B inhibitory activity as well as good TC-PTP inhibitory activity. These results established the potential for peptide-based inhibitors of PTP1B and TC-PTP to enhance their in vivo anti-T2DM efficacy and could provide a proof-of-concept for PTP1B/TC-PTP dual targeting as a therapeutic approach for T2DM.…”

“…Notably, a recent study found that combined intranasal targeting of hypothalamic PTP1B and TC-PTP reinstated leptin and insulin sensitivity and promoted weight loss in obesity . Another report showed that PTP1B/TC-PTP dual inhibitors could potentially emerge as a promising avenue for the development of drugs for the treatment of metabolic disorders, including type 2 diabetes mellitus (T2DM), obesity, and hyperphagia. Moreover, the proteolysis-targeting chimera approach , has been adopted to transform the PTP1B/TC-PTP dual inhibitors into degraders for both PTP1B and TC-PTP .…”

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

“…2 As shown in Figure 1, some of the cinnoline-containing compounds are reported as inhibitors of phosphoinositide 3kinase (PI3K), 3 Bruton's tyrosine kinase (BTK), 4 human neutrophil elastase (HNE), 5 protozoan parasite growth, 6 c-MET kinase, 7 ataxia telangiectasia mutated (ATM), 8 colonystimulating factor 1 receptor (CSF-1R), 9 phosphodiesterase 10A (PDE-10A), 10 leucine-rich repeat kinase 2 (LRRK-2), 11 and scytalone dehydratase (SD), 12 and also described as the anti-inflammatory agent, 13 dual non-acidic anti-inflammatory− antibacterial agent, 14 binding selective liver X receptor β (LXRβ) agonist, 15 (PTP1B)/T-cell protein phosphotyrosine phosphatase (TC-PTP). 17 The importance of cinnoline-based molecules in medicinal chemistry has caused the synthesis of cinnoline nucleus and cinnoline-containing heterocyclic scaffolds in the spotlight. In this regard, the design and/or use of simple and efficient synthetic strategies for the preparation of such precious compounds is worthwhile.…”

“…Cinnoline (also known as benzo­[ c ]­pyridazine, 1,2-benzodiazine, and 1,2-diazanaphthalene) is one of the most valuable fused heterocyclic systems, which exhibits a broad spectrum of pharmacological activities, and interestingly some of them are under evaluation in clinical trials . As shown in Figure , some of the cinnoline-containing compounds are reported as inhibitors of phosphoinositide 3-kinase (PI3K), Bruton’s tyrosine kinase (BTK), human neutrophil elastase (HNE), protozoan parasite growth, c-MET kinase, ataxia telangiectasia mutated (ATM), colony-stimulating factor 1 receptor (CSF-1R), phosphodiesterase 10A (PDE-10A), leucine-rich repeat kinase 2 (LRRK-2), and scytalone dehydratase (SD), and also described as the anti-inflammatory agent, dual non-acidic anti-inflammatory–antibacterial agent, binding selective liver X receptor β (LXR-β) agonist, mGlu 7 positive allosteric modulator (PAM), and dual inhibitor of protein phosphotyrosine phosphatase 1B (PTP1B)/T-cell protein phosphotyrosine phosphatase (TC-PTP) …”