Recent Advances in the Development of Protein Tyrosine Phosphatase 1B Inhibitors for Type 2 Diabetes

Abstract

Diabetes mellitus is the most serious and prevalent metabolic disorders worldwide, complications of which can decrease significantly the quality of life and contribute to premature death. Resistance to insulin is a predominant pathophysiological factor of Type 2 diabetes (T2D). Protein tyrosine phosphatase 1B (PTP1B) is an important negative factor of insulin signal and a potent therapeutic target in T2D patients. This review highlights recent advances (2012-2015) in research related to the role of PTP1B in signal transduction processes implicated in pathophysiology of T2D, and novel PTP1B inhibitors with an emphasis on their chemical structures and modes of action.

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

“…11) Most of the inhibitors with an acid moiety are considered to compete with a substrate, pTyr at the catalytic site, and, thus, may have low PTP1B selectivity and be directly influenced by the concentrations of substrates. Non-competitive inhibitors without a carboxyl or phosphonate group have recently been reported to interact with the allosteric site of PTP1B.…”

“…[14][15][16][17] Carboxyl types of inhibitors appear to compete with the substrate at the catalytic site, resulting in relatively low PTP1B selectivity because the catalytic site is similar among PTPs. 11,18) Although JTT-551 with a carboxyl moiety exhibited modest activity and antidiabetic effects in diabetic mice, clinical development was suspended possibly due to low efficacy in patients. 19) In order to achieve high PTP1B selectivity, allosteric inhibitors without a carboxyl moiety have been synthesized and exhibited modest activity and efficacy (Trodusquemine and compound IV in Fig.…”

“…1,2,[7][8][9] Reported allosteric inhibitors consist of two or more aromatic rings connected via acyl, ether, or alkyl linkers, and exhibit relatively weak activity. 11) In the present study, we synthesized a series of benzoylsulfonamide derivatives with a linker and aromatic ring. Structure-activity relationships were discussed and 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl) benzamide (compound 18K) was selected * To whom correspondence should be addressed.…”

“…1,2,[7][8][9] Based on this background, PTP1B has been attracting attention as a potential therapeutic target and a large number of PTP1B inhibitors have been reported as candidates for anti-diabetic and anti-obesity drugs. 1,[10][11][12] Classically, some types of vanadates have been shown to inhibit PTP1B and exert insulinomimetic actions. 10) Small molecule synthetic inhibitors started from peptidyl phosphonates, which mimic the substrate, a phosphorylated tyrosine (pTyr).…”

“…1). 11,20) Trodusquemine is a naturally-occurring spermine derivative and an allosteric PTP1B inhibitor. 21,22) Although its parenteral administration of trodusquamine showed anti-diabetic and anti-obesity effects in mice, its clinical development was discontinued.…”