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Structure‐Based Optimization of Protein Tyrosine Phosphatase‐1 B Inhibitors: Capturing Interactions with Arginine 24
Author(s) -
Wan ZhaoKui,
Lee Jinbo,
Hotchandani Rajeev,
Moretto Alessandro,
Binnun Eva,
Wilson Douglas P.,
Kirincich Steve J.,
Follows Bruce C.,
Ipek Manus,
Xu Weixin,
JosephMcCarthy Diane,
Zhang YanLing,
Tam May,
Erbe David V.,
Tobin James F.,
Li Wei,
Tam Steve Y.,
Mansour Tarek S.,
Wu Junjun
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800188
Subject(s) - hydrogen bond , arginine , substituent , protein tyrosine phosphatase , chemistry , stereochemistry , binding site , derivative (finance) , tyrosine , combinatorial chemistry , biochemistry , molecule , amino acid , organic chemistry , financial economics , economics
Further optimization efforts on the previously disclosed PTP‐1B inhibitor 1 a led to the discovery of a new series of potent compounds, for example derivative 33 , which targeted the second phosphotyrosine binding pocket near the catalytic site. In the new series, the N ‐sulfonylpiperidine group of 1 a was replaced with a smaller substituent, capable of forming a new hydrogen bond interaction with arginine 24. The series reported here maintains the binding mode of 1 a and has the added advantages of a lower molecular weight, smaller polar surface area, and fewer rotatable bonds.