Insight into the protein tyrosine phosphatase 1B (PTP1B) inhibitory activity of pyrazoles

Diabetes mellitus (DM) is a long-term chronic condition characterized by hyperglycemia, being one of the biggest global health emergencies of the 21^st century. Type 2 DM is the most common form of DM, representing 90-95% of patients with DM. Insulin resistance is the earliest detectable abnormality and the characteristic feature in individuals with type 2 DM. Protein tyrosine phosphatase 1B (PTP1B) has been emerging as a promising drug target for the management of type 2 DM. PTP1B plays an important role as a negative regulator of the insulin signaling pathway, which act by dephosphorylation of the insulin receptor and insulin receptor substrates, suppressing the insulin signaling cascade. In this study, a panel of 22 new potential PTP1B inhibitor pyrazoles were evaluated against human PTP1B activity. Using a microanalysis screening system, the methodology used was based on the inhibition of the hydrolysis of the substrate p-nitrophenyl phosphate (pNPP) in p-nitrophenolate, followed by reading of the absorbance at 405 nm. The mechanism of inhibition was determined graphically by Lineweaver-Burk plots and by non-linear least squares regression using the Solver^TM supplement of Excel Microsoft Office^TM. The obtained results allowed the establishment of a structure-activity rationale where the pyrazoles 5-(2-hydroxyphenyl)-3-{2-[3-(4-nitrophenyl)-1,2,3,4-tetrahydronaphthyl]}-1-phenylpyrazole and 3-(2-hydroxyphenyl)-5-{2-[3-(4-methoxyphenyl)]-naphthyl}pyrazole excelled as the most potent inhibitors of PTP1B activity, through non-competitive inhibition mechanism. The presence of additional benzene rings in the pyrazole scaffold seems to favour the inhibitory activity. Moreover, the used approach represents a significant launch for the design and assessment of novel PTP1B inhibitors.