title: 3-Phenylpropanoic acid-based phosphotyrosine (pTyr) mimetics: hit evolution to a novel orally active protein tyrosine phosphatase 1B (PTP1B) inhibitor.
abstract: Protein tyrosine phosphatase 1B (PTP1B) is a promising therapeutic target for type 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 in 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 in 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.
authors.affiliation: Beijing Key Laboratory of Active Substance Discovery & Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xiannongtan Street, Beijing 100050 (China).
authors.forename: Yan-Bo
authors.initials: YB
authors.lastname: Tang
authors.forename: Jun-Zheng
authors.initials: JZ
authors.lastname: Liu
authors.forename: Shu-En
authors.initials: SE
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: Feilin
authors.initials: F
authors.lastname: Nie
authors.forename: Jin-Ying
authors.initials: JY
authors.lastname: Tian
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Hu
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D032701:Biomimetics; D001786:Blood Glucose / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D010666:Phenylpropionates / Q000737:chemistry*; D019000:Phosphotyrosine / Q000737:chemistry*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D010666:Phenylpropionates; D019000:Phosphotyrosine; C035253:3-phenylpropionic acid; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: 3-phenylpropanoic acids; inhibitors; medicinal chemistry; protein tyrosine phosphatase 1B; type 2 diabetes