Synthesis and PTP1B inhibition of novel 4-aryl-1-oxa-9-thiacyclopenta[b]fluorenes.
Novel 4-aryl-1-oxa-9-thiacyclopenta[b]fluorenes were designed, synthesized, and evaluated as inhibitors of the protein tyrosine phosphatase, PTP1B. Compounds 3 (IC50 = 284 nM) and 4 (IC50 = 74 nM), showed nanomolar potency against PTP1B (TRDI(P)YETD(P)Y(P)YRK as substrate). Compound 4 also lowered insulin in the diabetic ob/ob mouse at a dose of 10 mg/kg/day, p.o.
Wyeth-Ayerst Research, Inc., Princeton, NJ 08543-8000, USA. wrobelj@war.wyeth.com
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J
Wrobel
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Li
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Sredy
D R
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Sawicki
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Seestaller
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Sullivan
D000595:Amino Acid Sequence; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001572:Benzofurans; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D009842:Oligopeptides; D013876:Thiophenes; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse