Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-10
2002-06-25
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S533000, C514S538000, C514S562000, C548S546000, C558S030000, C560S037000, C560S042000, C562S442000, C562S451000
Reexamination Certificate
active
06410585
ABSTRACT:
FIELD OF THE INVENTION
The present invention comprises small molecular weight, non-peptidic inhibitors of Protein Tyrosine Phosphatase 1 (PTP1) which are useful for the treatment and/or prevention of Non-Insulin Dependent Diabetes Mellitus (NIDDM).
BACKGROUND OF THE INVENTION
The mechanism of insulin action depends critically upon the phosphorylation of tyrosine residues in several proteins in the insulin signaling cascade. Enzymes that dephosphorylate these proteins, protein tyrosine phosphatases (PTPs), are important negative regulators of insulin action. Therefore, the use of specific PTP inhibitors may therapeutically enhance insulin action.
The insulin resistance that is central to noninsulin-dependent diabetes mellitus (NIDDM) appears to involve a defect in an early process in insulin signal transduction rather than a structural defect in the insulin receptor itself. (J. M. Olefsky, W. T. Garvey, R. R. Henry, D. Brillon, S. Matthai and G. R. Freidenberg, G. R. (1988).) Cellular mechanisms of insulin resistance in non-insulin-dependent (Type II) diabetes. (Am. J. Med. 85: Suppl. 5A, 86-105.) A drug that improved insulin sensitivity would have several advantages over traditional therapy of NIDDM using sulfonylureas, which do not alleviate insulin resistance but instead compensate by increasing insulin secretion.
The binding of insulin to the &agr;-subunits of the insulin receptor permits the &bgr;-subunits to catalyze phosphorylation of target proteins on tyrosine residues. There are 22 tyrosine residues in each insulin receptor &bgr;-subunit itself and autophosphorylation of at least 6 of these tyrosines, in 3 distinct domains, is known to be involved in insulin action. (C. R. Kahn (1994) Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 43: 1066-1084.) Autophosphorylation of Tyr
960
in the juxtamembrane domain is important for receptor internalization and for the interaction of the receptor with downstream signaling molecules such as insulin receptor substrate 1 (IRS-1).) (T. J. O'Neill, A. Craparo and T. A. Gustafson (1994) Characterization of an interaction between insulin receptor substrate 1 and the insulin receptor by using the two-hybrid system. Mol. Cell Biol. 14: 6433-6442.) Autophosphorylation of tyrosine residues 1146, 1150 and 1151 in the regulatory domain permits continued tyrosine kinase activity of &bgr;-subunits, even after insulin has dissociated from the &agr;-subunits, and activates the kinase toward other protein substrates. (R. Herrera and O. M. Rosen (1986) Autophosphorylation of the insulin receptor in vitro: designation of phosphorylation sites and correlation with receptor kinase activation. J. Biol. Chem. 261: 11980-11985.) Deletion of autophosphorylation sites at Tyr
1316
and Tyr
1322
in the C-terminal domain attenuates the metabolic actions of insulin, but augments its mitogenic actions. (H. Maegawa, D. McClain, G. Freidenberg, J. Olefsky, M. Napier, T. Lipari, T. Dull, J. Lee, and A. Ullrich (1988) Properties of a human insulin receptor with a COOH-terminal truncation. II. Truncated receptors have normal kinase activity but are defective in signaling metabolic effects. J. Biol. Chem. 263: 8912-8917.) (Y. Takata, N. J. G. Webster, and J. M. Olefsky (1991) Mutation of the two carboxyl-terminal tyrosines results in an insulin receptor with normal metabolic signaling but enhanced mitogenic signaling properties. J. Biol. Chem. 266: 9135-9139.) Dephosphorylation of these autophosphorylated sites occurs rapidly in vivo, suggesting that a protein tyrosine phosphatase (PTPase) is involved in terminating insulin action. A compound that inhibited this PTPase, therefore, should potentiate insulin action. Indeed, vanadate potentiates insulin action, at least in part, by such a mechanism (Y. Schechter (1990). Insulin-mimetic effects of vanadate. Possible implications for future treatment of diabetes. Diabetes 39: 1-5.) The PTPase(s) that act on the insulin receptor, however, has not been identified definitively.
It has been estimated that the human genome encodes as many as 500 PTP enzymes (T. Hunter (1995) Protein kinases and phosphatases: The Yin and Yang of protein phosphorylation and signaling. Cell 80: 225-236), but less than 100 have been identified and have been grouped into 4 sub-families (E. A. Fauman and M. A. Saper (1996) Structure and function of the protein tyrosine phosphatases. Trends Biochem. Sci. 21: 413-417.) Members of the tyrosine-specific PTP sub-family are further divided into the receptor PTPases (such as CD45 and LAR) which typically have a large variable extracellular domain, a single transmembrane spanning region, and two intracellular phosphatase catalytic domains and the non-receptor PTPases. This latter group includes PTP that resemble PTP1. (D. A. Pot and J. E. Dixon (1992) A thousand and two protein tyrosine phosphatases. Biochim. Biophys. Acta 1136:35-43.) There is data to support the proposition that the insulin receptor PTPase may be PTP1-like. For instance, an insulin-dependent association of PTP1 with insulin receptors has been described. (D. Bandyopadhyay, A. Kursari, K. A. Kenner, F. Liu, J. Chemoff, T. A. Gustafson, J. Kusari (1997) Protein-tyrosine phosphatase 1B complexes with the insulin receptor in vivo and is tyrosine-phosphorylated in the presence of insulin. J. Biol. Chem. 272: 1639-1645; and L. Seely, et al. (1996) Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes 45: 1379.) Furthermore, PTP1 dephosphorylates purified insulin receptors sequentially in the order observed in vivo (i.e., Tyr
1150
=Tyr
1151
>Tyr
1146
), (C. Ramachandran, R. Aebersold, N. Tonks and D. A. Pot (1992) Sequential dephosphorylation of a multiply phosphorylated insulin receptor peptide by protein tyrosine phosphatases. Biochemistry 31: 4232-4238) and insulin acutely increases PTP1 mRNA in hepatoma cells. (N. Hashimoto and B. J. Goldstein (1992) Differential regulation of mRNAs encoding three protein-tyrosine phosphatases by insulin and activation of protein kinase C. Biochem. Biophys. Res. Commun. 188: 1305-1311.) Insulin resistance induced in Rat 1 fibroblasts by high glucose (27 mM) is preceded by an approximate doubling of cytosolic PTP1 activity that is blocked by the insulin-sensitizer, pioglitazone. (H. Maegawa, R. Ide, M. Hasegawa, S. Ugi, K. Egawa, M. Iwanishi, R. Kikkawa, Y. Shigeta, and A. Kashiwagi (1995) Thiazolidinedione derivatives ameliorate high glucose-induced insulin resistance via the normalization of protein tyrosine phosphatase activities. J. Biol. Chem. 270: 7724-7730.) Thus, a specific inhibitor of PTP1 could be used to potentiate insulin action. While there are no known small molecules that specifically inhibit PTP1, it was found that osmotic loading of hepatoma cells with neutralizing antibodies against PTP1b (the human homologue of rat PTP1) resulted in increased autophosphorylation of insulin receptors and phosphorylation of IRS-1 in response to insulin. (F. Ahmad, P.-M. Li, J. Meyerovitch, and B. J. Goldstein (1995) Osmotic loading of neutralizing antibodies demonstrates a role for PTPase 1B in negative regulation of the insulin signaling pathway. Diabetes 44: Suppl. 1 104A.) See also B. J. Goldstein (1993) Regulation of insulin receptor signaling by protein-tyrosine dephosphorylation. Receptor 3: 1-15.)
INFORMATION DISCLOSURE
International Publication No. WO 96/30332, “O-Malonyltyrosyl Compounds, O-Malonyltyrosyl Compound-Containing Peptides, and Uses thereof,” published Oct. 3, 1996, disclose non-phosphorus containing O-malonyltyrosyl compounds, derivatives thereof, uses of the O-malonyltyrosyl compounds in the synthesis of peptides, and O-malonyltyrosyl compound-containing peptides. The O-malonyltyrosyl compounds and O-malonyltyrosyl compound-containing peptides are disclosed as being useful as inhibitors of protein-tyrosine phosphatase; however, no specific non-peptidic compounds or data is disclosed.
International Publication No. WO 96/23813, “Peptides and Compounds that Bind to SH2 Domains,” published Aug. 8, 1996, discloses
Barf Tjeerd
Bleasdale John E.
Larsen Scott D.
Liljebris Charlotta
May Paul D.
Fish & Richardson P.C.
Gerstl Robert
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