Novel Non-carboxylate Benzoylsulfonamide-Based Protein Tyrosine Phosphatase 1B Inhibitors with Non-competitive Actions

Abstract

A novel series of benzoylsulfonamide derivatives were synthesized and biologically evaluated. Among them, 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzamide (compound 18K) was identified as a protein tyrosine phosphatase 1B (PTP1B) inhibitor with potent and selective inhibitory activity against PTP1B (IC 50 0.25 µM). Compound 18K functioned as a non-competitive inhibitor and bound to the allosteric site of PTP1B. It also showed high oral absorption in mice (the maximum drug concentration (C max ) 45.5 µM at 30 mg/kg), rats (C max 53.6 µM at 30 mg/kg), and beagles (C max 37.8 µM at 10 mg/kg), and significantly reduced plasma glucose levels at 30 mg/kg/d (per os (p.o.)) for one week with no side effects in db/db mice. In conclusion, the substituted benzoylsulfonamide was shown to be a novel scaffold of a noncompetitive and allosteric PTP1B inhibitor, and compound 18K has potential as an efficacious and safe antidiabetic drug as well as a useful tool for investigations of the physiological and pathophysiological effects of allosteric PTP1B inhibition.Key words benzoylsulfonamide; protein tyrosine phosphatase 1B; allosteric inhibitor; non-competitive inhibitor; db/db mouse; Sprague-Dawley rat In various cellular signaling pathways, protein tyrosine kinases (PTKs) mediate the phosphorylation of tyrosine residues in a number of proteins, while protein tyrosine phosphatases (PTPs) de-phosphorylate phosphorylated tyrosine.

2-Acyl-3-carboxyl-tetrahydroisoquinoline Derivatives: Mixed-Type PTP1B Inhibitors without PPARγ Activation

“…It also moderately attenuated elevations in plasma glucose levels by 14.9% at 10 mg/kg/d and significantly by 41.3% at 30 mg/kg/d in the oral glucose tolerance test. The mode of inhibition (competitive, mixed, or non-competitive) that is the most suitable for therapeutic use has not yet been established: CX08005 (competitive), 31) JTT-551 (mixed), 27) and KY-226 (non-competitive) 32) have all been reported to exert potent anti-diabetic effects experimentally. Compound 17u has high water solubility (797 µg/mL) and, thus, may be widely used as oral, injection and eye drop formulations for the treatment of diseases mediated by PTP1B.…”

“…A number of structurally and mechanistically different inhibitors have recently been reported: carboxyl-type and non-carboxyl-type inhibitors as well as competitive-type, non-competitive-type, and mixed-type inhibitors. [22][23][24][25]31) Mixed-type inhibition is a mixture of competitive and non-competitive inhibition. We also discovered the non-carboxyl type non-competitive PTP1B inhibitor KY-226 without PPARγ activation, which binds to the allosteric site of PTP1B 32) (Fig.…”

Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine

“…A promising alternative arises from the presence of allosteric regions on the surface of PTP1B; effective interactions with these sites can be established by less polar ligands, potentially endowed with more favorable pharmacokinetics than conventional catalytic site-directed inhibitors. Moreover, these non-catalytic regions comprise nonconserved amino acid residues, which provide an opportunity for developing selective PTP1B inhibitors [55,[68][69][70][71][72].…”

“…amino acid residues, which provide an opportunity for developing selective PTP1B in itors [55,[68][69][70][71][72].…”

Discovery and evaluation of biphenyl derivatives of 2‐iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity

“…Resulting molecules are expected to have better drug‐likeliness and pharmacokinetic profile than molecules constructed from linked or fused pharmacophores. A number of allosteric PTP1B inhibitors comprise biphenyl fragment linked with aromatic core, for example, sulfonamide 4 (Ito et al, 2018; Morishita et al, 2017) and chromene 5 (Shim et al, 2003; Figure 2). A range of similar compounds also reviewed in (Thareja et al, 2012).…”