Structure-based optimization of protein tyrosine phosphatase 1B inhibitors: from the active site to the second phosphotyrosine binding site.
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.
Wilson
Douglas P
DP
Chemical and Screening Sciences, and Cardiovascular and Metabolic Diseases, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.
Wan
Zhao-Kui
ZK
Xu
Wei-Xin
WX
Kirincich
Steven J
SJ
Follows
Bruce C
BC
Joseph-McCarthy
Diane
D
Foreman
Kenneth
K
Moretto
Alessandro
A
Wu
Junjun
J
Zhu
Min
M
Binnun
Eva
E
Zhang
Yan-Ling
YL
Tam
May
M
Erbe
David V
DV
Tobin
James
J
Xu
Xin
X
Leung
Louis
L
Shilling
Adam
A
Tam
Steve Y
SY
Mansour
Tarek S
TS
Lee
Jinbo
J
D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D020134:Catalytic Domain; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D006207:Half-Life; D022781:Hepatocytes; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D019000:Phosphotyrosine / Q000737:chemistry / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
D013876:Thiophenes; D019000:Phosphotyrosine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; C516610:Ptpn1 protein, rat