title: Design, synthesis and insulin-sensitising effects of novel PTP1B inhibitors.
abstract: Fifteen novel sulfathiazole-related compounds were designed as PTP1B inhibitors based on a previously reported allosteric inhibitor (1) of PTP1B. These compounds were synthesized and evaluated against human recombinant PTP1B. Six compounds (3, 4, 8 and 14-16) exhibited significant inhibitory activity against PTP1B. The most active compound (16) showed IC50 value of 3.2 μM and kinetic analysis indicated that it is a non-competitive inhibitor of PTP1B. Furthermore, compound 16 demonstrated excellent selectivity to PTP1B over other PTPs. It also displayed in vivo insulin sensitizing effect in the insulin resistant mice.
authors.affiliation: Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Yan-Bo
authors.initials: YB
authors.lastname: Tang
authors.forename: Dianyun
authors.initials: D
authors.lastname: Lu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Chun
authors.initials: C
authors.lastname: Hu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Jin-Ying
authors.initials: JY
authors.lastname: Tian
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013432:Sulfathiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D011994:Recombinant Proteins; D013432:Sulfathiazoles; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1