Isoxazole carboxylic acids as protein tyrosine phosphatase 1B (PTP1B) inhibitors Hongyu Zhao, a, * Gang Liu, a Zhili Xin, a Michael D. Serby, a Zhonghua Pei, a Bruce G. Szczepankiewicz, a Philip J. Hajduk, b Cele Abad-Zapatero, b Charles W. Hutchins, b Thomas H. Lubben, a Stephen J. Ballaron, a Deanna L. Haasch, a Wiweka Kaszubska, a Cristina M. Rondinone, a James M. Trevillyan a and Michael R. Jirousek a, a Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA b Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA Received 9 August 2004; accepted 31 August 2004 Available online 18 September 2004 Abstract—Guided by X-ray crystallography, we have extended the structure–activity relationship (SAR) study on an isoxazo oxylic acid-based PTP1B inhibitor (1) and more potent and equally selective (>20-fold selectivity over the highly homologo PTPase, TCPTP) PTP1B inhibitors were identified. Inhibitor 7 demonstrated good cellular activity against PTP1B in COS 7 ce Ó 2004 Elsevier Ltd. All rights reserved. Protein tyrosine phosphatase 1B (PTP1B), an intracellu- lar PTPase, has been implicated in negative regulation of the insulin and leptin signaltransduction pathways among otherbiologicalfunctions. 1 Studiesfrom two laboratories have shown that PTP1B knockout mice ex- hibit the phenotypes of increased insulin sensitivity, im- proved glucose tolerance, and resistance to diet-induced obesity. 2,3 In a more therapeutically relevant study, Zin- ker et al. have demonstrated that a PTP1B antisense oligonucleotide normalizes blood glucose and improves insulin sensitivity in diabetic mice via a mechanism of lowering PTP1B protein expression. 4 A synthetic small molecule that selectively inhibits PTP1B action is ex- pected to have similar beneficial effects in type 2 diabetic and obesity patients. Two major challenges in developing potential therapeu- tics targeting PTP1B are selectivity and cell permeabil- ity. The X-ray crystal structurerevealedthat the PTP1B catalytic site and vicinal binding sites are highly hydrophilic and homologous to other PTPases. 5,6 These structuralfeatureswere furthersubstantiated by that fact that most known PTP1B inhibitors are large (MW > 500) and hydrophilic molecules containing mul- tiple acid and peptide groups. 7 Nonetheless, cell perme- able PTP1B inhibitorshave been reported in several laboratories. 8 High selectivity over PTPases other than TCPTP 9 has been routinely achieved, but only a few compounds showed moderate selectivity over TCPTP (10-fold). 10 We have previously reported the discovery of isoxazole carboxylicacid-based PTP1B inhibitorssuch as 1. 11 O MeO O OH F N O O HO 1 binds to the catalytic site binds to site 2 linker K i 6.9µ M (PTP1B), K i 164µ M (TCPTP) 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.08.063 Keywords: PTP1B; Selective; Cell permeable. * Corresponding author. Tel.: +1 847 935 4566; fax: +1 847 938 1674; e-mail: hongyu.zhao@abbott.com Present address: Pfizer GlobalR&D, La Jolla Laboratories,10770 Science Center Drive, San Diego, CA 92121-1187, USA. Bioorganic & Medicinal Chemistry Letters 14 (2004) 5543–5546