ABSTRACT
Protein tyrosine phosphataseâ 1B (PTP1B) is a promising therapeutic target for typeâ 2 diabetes. Herein, we report the evolution of a previously identified 3-phenylpropanoic acid-based PTP1B inhibitor to an orally active lead compound. A series of 3-phenylpropanoic acid-based PTP1B inhibitors were synthesized, and three of them, 3-(4-(9H-carbazol-9-yl)phenyl)-5-(3,5-di-tert-butyl-4-methoxyphenyl)-5-oxopentanoic acid (9), 3-(4-(9H-carbazol-9-yl)phenyl)-5-(4'-bromo-[1,1'-biphenyl]-4-yl)-5-oxopentanoic acid (10) and 3-(4-(9H-carbazol-9-yl)-2-fluorophenyl)-5-(4-cyclohexylphenyl)-5-oxopentanoic acid (16), showed IC50 values at sub-micromolar level. Further inâ vivo evaluation indicated the sodium salt of 9 not only exhibited significant insulin-sensitizing and hypoglycemia effects, but also decreased the serum levels of triglyceride and total cholesterol in high-fat-diet-induced insulin resistance model mice. Preliminary inâ vivo pharmacokinetic studies on the sodium salt of 9 revealed its pharmacokinetic profile after oral administration in rats. These results provide proof-of-concept for the dual effects of PTP1B inhibitors on both glucose and lipid metabolisms.
Subject(s)
Biomimetic Materials/administration & dosage , Biomimetic Materials/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phenylpropionates/chemistry , Phosphotyrosine/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Animals , Biomimetic Materials/chemistry , Biomimetics , Blood Glucose/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Humans , Mice , Molecular Structure , Obesity/drug therapy , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Rats , Structure-Activity RelationshipABSTRACT
An integrated molecular design strategy combining pharmacophore recognition and scaffold hopping was exploited to discover novel PTP1B inhibitors based on the known PTP1B inhibitor Ertiprotafib. A composite pharmacophore model was proposed from the interaction mode of Ertiprotafib, and 21 diverse molecules from five distinct structural classes were designed and synthesized accordingly. New compounds with considerable inhibition against PTP1B were identified from each series, and the most active compound 3a showed IC50 value of 1.3 µmol L(-1) against human recombinant PTP1B. Docking study indicated that the new inhibitors assumed binding modes similar to that of Ertiprotafib.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Phenylpropionates/chemistry , Phenylpropionates/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Thiophenes/chemistry , Thiophenes/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Phenylpropionates/chemical synthesis , Thiophenes/chemical synthesisABSTRACT
Protein tyrosine phosphatase (PTP) 1B is a potential target for the treatment of diabetes and obesity. Phosphotyrosine (pTyr) is the substrate for PTP1B dephosphorylation. Malonic acid moiety was used herein as a mimic of the phosphate group in pTyr, and novel malonic acid derivatives 1-7 were designed, synthesized and evaluated as PTP1B inhibitors. Results from enzymatic assays indicated that compounds 3 and 4 exhibited potent inhibition against human recombinant PTP1B with IC50 values of 7.66 and 1.88 micromol x L(-1), respectively.
