title: Synthesis and LAR inhibition of 7-alkoxy analogues of illudalic acid.
abstract: To obtain higher potency and specificity, a series of 7-alkoxy analogues of illudalic acid was synthesized on the base of structure-activity relationship (SAR). All of these compounds exhibited submicromolar inhibition of the enzyme when tested against human leukocyte common antigen-related phosphatase (LAR) (for example, for 15e, IC50 = 180 nmol x L(-1)). They represent the most potent small-molecule inhibitors of LAR so far. These analogues also display excellent selectivity for LAR over other protein tyrosine phosphatases (PTPs) except for the highly homologous PTPsigma. The compound 15f is of 120-fold selectivity for LAR versus PTP-1B inhibition. The development of potent enzyme-specific inhibitors is so important that they may serve both as tools to study the role of LAR and as therapeutic agents for treatment of type II diabetes.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy ofSciences, Shanghai 201203, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ling
authors.forename: Yue-Yang
authors.initials: YY
authors.lastname: Zhou
authors.forename: Zheng-Liang
authors.initials: ZL
authors.lastname: Cai
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Lan-Ping
authors.initials: LP
authors.lastname: Ma
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Jing-Kang
authors.initials: JK
authors.lastname: Shen
mesh_terms: D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D004791:Enzyme Inhibitors; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; C532762:illudalic acid