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Structure-based optimization of protein tyrosine phosphatase 1B inhibitors: from the active site to the second phosphotyrosine binding site.

Abstract：

:Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from the enzyme active site into the second phosphotyrosine binding site is described. Medicinal chemistry, guided by X-ray complex structure and molecular modeling, has yielded low nanomolar PTP1B inhibitors in an efficient manner. Compounds from this chemical series were found to be actively transported into hepatocytes. This active uptake into target tissues could be one of the possible avenues to overcome the poor membrane permeability of PTP1B inhibitors.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Wilson DP,Wan ZK,Xu WX,Kirincich SJ,Follows BC,Joseph-McCarthy D,Foreman K,Moretto A,Wu J,Zhu M,Binnun E,Zhang YL,Tam M,Erbe DV,Tobin J,Xu X,Leung L,Shilling A,Tam SY,Mansour TS,Lee J

doi

10.1021/jm0702478

subject

Has Abstract

pub_date

2007-09-20 00:00:00

pages

4681-98

issue

19

eissn

0022-2623

issn

1520-4804

journal_volume

50

pub_type

杂志文章

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