title: 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.
authors: Chemical and Screening Sciences, and Cardiovascular and Metabolic Diseases, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.
authors: Douglas P
authors: DP
authors: Wilson
authors: Zhao-Kui
authors: ZK
authors: Wan
authors: Wei-Xin
authors: WX
authors: Xu
authors: Steven J
authors: SJ
authors: Kirincich
authors: Bruce C
authors: BC
authors: Follows
authors: Diane
authors: D
authors: Joseph-McCarthy
authors: Kenneth
authors: K
authors: Foreman
authors: Alessandro
authors: A
authors: Moretto
authors: Junjun
authors: J
authors: Wu
authors: Min
authors: M
authors: Zhu
authors: Eva
authors: E
authors: Binnun
authors: Yan-Ling
authors: YL
authors: Zhang
authors: May
authors: M
authors: Tam
authors: David V
authors: DV
authors: Erbe
authors: James
authors: J
authors: Tobin
authors: Xin
authors: X
authors: Xu
authors: Louis
authors: L
authors: Leung
authors: Adam
authors: A
authors: Shilling
authors: Steve Y
authors: SY
authors: Tam
authors: Tarek S
authors: TS
authors: Mansour
authors: Jinbo
authors: J
authors: Lee
mesh_terms: 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
chemical_list: 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