Modification of the N-terminus of peptidomimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors: identification of analogues with cellular activity.
Low molecular weight peptidomimetic compounds based on O-malonyl tyrosine and O-carboxymethyl salicylic acid are potent inhibitors of PTP1B. Modifications of the N-terminal Boc-Phe moiety were undertaken in an effort to improve physical chemical properties and to achieve cellular activity. Although Phe ultimately proved to be the optimal N-terminal amino acid, several viable replacements for the Boc group were identified, two of which afforded analogues that were effective at enhancing the insulin-stimulated uptake of 2-deoxyglucose by L6 myocytes.
Larsen
Scott D
SD
Medicinal Chemistry Research, Pharmacia Corporation, 333 Portage Street, Kalamazoo, MI 49007, USA. scott.d.larsen@pharmacia.com
Stevens
F Craig
FC
Lindberg
Thomas J
TJ
Bodnar
Paul M
PM
O'Sullivan
Theresa J
TJ
Schostarez
Heinrich J
HJ
Palazuk
Barbara J
BJ
Bleasdale
John E
JE
D000818:Animals; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D018716:Molecular Mimicry; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051381:Rats; D012459:Salicylates / Q000737:chemistry* / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D018909:src Homology Domains
D004791:Enzyme Inhibitors; D007328:Insulin; D012459:Salicylates; C093257:malonyltyrosine; D014443:Tyrosine; D010649:Phenylalanine; D003847:Deoxyglucose; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516610:Ptpn1 protein, rat