Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
2000-07-26
2002-12-10
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
C514S598000
Reexamination Certificate
active
06492428
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention provides methods of use and pharmaceutical compositions for related genera of low molecular weight compounds comprising optionally substituted iminoquinone and orthoquinoid ring systems. The compounds have MIF (macrophage migration inhibitory factor) antagonist activity and find utility as such. For example, the MIF antagonists are useful in methods for treating a variety of diseases involving inflammatory activity or pro-inflammatory cytokine responses, such as autoimmune diseases, asthma, arthritis, EAE, ARDS (acute respiratory distress syndrome) and various forms of sepsis and septic shock, and other conditions characterized by underlying MIF responses including, for instance, tumor growth and neovascularization.
BACKGROUND OF THE INVENTION
Macrophage migration inhibitory factor (MIF) is one of the earliest described cytokines, and is an immunoregulatory protein with a wide variety of cellular and biological activities (for reviews see: Swope & Lolis,
Rev. Physiol. Biochem. Pharmacol
. 139:1-32, 1999; Metz & Bucala,
Adv. Immunol
. 66:197-223, 1997; and Bucala,
FASEB J
. 14:1607-1613, 1996). Originally, MIF was found to be secreted by activated lymphoid cells, to inhibit the random migration of macrophages, and to be associated with delayed-type hypersensitivity reactions (George & Vaughan,
Proc. Soc. Exp. Biol. Med
. 111:514-521, 1962; Weiser et al.,
J. Immunol
. 126:1958-1962, 1981; Bloom & Bennett, Science, 153:80-82, 1966; David,
Proc. Natl. Acad. Sci
. USA 56:72-77, 1966). MIF was also shown to enhance macrophage adherence, phagocytosis and tumoricidal activity (Nathan et al.,
J. Exp. Med
. 137:275-288, 1973; Nathan et al.,
J. Exp. Med
. 133:1356-1376, 1971; Churchill et al.,
J. Immunol
. 115:781-785, 1975). Unfortunately, many of these early studies used mixed-culture supernatants that were shown later to contain other cytokines, such as IFN-&ggr; and IL-4 that also have macrophage migration inhibitory activity (McInnes & Rennick,
J. Exp. Med
. 167:598-611, 1988; Thurman et al.,
J. Immunol
. 134:305-309, 1985) making the historical attribution of specific biological activities to the single protein now defined as MIF somewhat problematic. The availability of recombinant MIF has allowed for confirmation of these biological activities, and for the identification of additional activities.
Recombinant human MIF was originally cloned from a human T cell library (Weiser et al.,
Proc. Natl. Acad. Sci
. USA 86: 7522-7526, 1989), and was shown to activate blood-derived macrophages to kill intracellular parasites and tumor cells in vitro, to stimulate IL-1&ggr; and TNF&agr; expression, and to induce nitric oxide synthesis (Weiser et al.,
J. Immunol
. 147:2006-2011, 1991; Pozzi et al.,
Cellular Immunol
. 145:372-379, 1992; Weiser et al.,
Proc. Natl. Acad. Sci
. USA 89:8049-8052, 1992; Cunha et al.,
J. Immunol
. 150:1908-1912, 1993). While the conclusions available from several of these early reports are confounded by the presence of a bioactive mitogenic contaminant in the recombinant MIF preparations used, the potent pro-inflammatory activities of MIF have been re-defined in other studies that do not suffer from this complicating factor (reviewed in Bucala, The FASEB Journal 10:1607-1613, 1996).
More recent MIF studies have capitalized on the production of recombinant MIF in purified form as well as the development of MIF-specific polyclonal and monoclonal antibodies to establish the biological role of MIF in a variety of normal homeostatic and pathophysiological settings (reviewed in Rice et al.,
Annual Reports in Medicinal Chemistry
33:243-252, 1998). Among the most important insights of these later reports has been the recognition that MIF not only is a cytokine product of the immune system, but also is a hormone-like product of the endocrine system, particularly the pituitary gland. This work has underscored the potent activity of MIF as a counter-regulator of the anti-inflammatory effects of the glucocorticoids (both those endogenously released and those therapeutically administered), with the effect that the normal activities of glucocorticoids to limit and suppress the severity of inflammatory responses are inhibited by MIF. The endogenous MIF response is thus seen as a cause or an exacerbative factor in a variety of inflammatory diseases and conditions (reviewed in Donnelly and Bucala,
Molecular Medicine Today
3:502-507, 1997).
MIF is now known to have several biological functions beyond its long-hypothesized association with delayed-type hypersensitivity reactions. For example, as mentioned above, MIF released by macrophages and T cells acts as a pituitary mediator in response to physiological concentrations of glucocorticoids (Bucala,
FASEB J
. 14:1607-1613, 1996). This leads to an overriding effect of glucocoticoid immunosuppressive activity through alterations in TNF-&agr;, IL-1&bgr;, IL-6, and IL-8 levels. Additional biological activities of MIF include the regulation of stimulated T cells (Bacher et al.,
Proc. Natl. Acad. Sci
. USA 93:7849-7854, 1996), the control of IgE synthesis (Mikayama et al.,
Proc. Natl. Acad. Sci
. USA 90:10056-60, 1993), the functional inactivation of the p53 tumor suppressor protein (Hudson et al.,
J. Exp. Med
. 190:1375-1382, 1999), the regulation of glucose and carbohydrate metabolism (Sakaue et al.,
Mol. Med
. 5:361-371, 1999), and the attenuation of tumor cell growth and tumor angiogenesis (Chesney et al.,
Mol Med
. 5:181-191, 1999; Shimizu et al.,
Biochem. Biophys. Res. Commun
. 264:751-758, 1999).
MIF shares significant sequence homology (36% identity) with D-dopachrome tautomerase, and MIF has enzymatic activity to catalyze the tautomerization of the non-physiological substrates D-dopachrome (Rosengren et al.,
Mol. Med
. 2:143-149, 1996) and L-dopachrome methyl ester (Bendrat et al.,
Biochemistry
, 36:15356-15362, 1997) (FIG.
1
A). Additionally, phenylpyruvic acid and p-hydroxyphenylpyruvic acid (Rosengren et al.,
FEBS Letter
, 417:85-88, 1997), and 3,4-dihydroxyphenylaminechrome and norepinephrinechrome (Matsunaga et al.,
J. Biol. Chem
., 274:3268-3271, 1999) are MIF substrates, although it is not known if tautomerization of any of these agents comprises a natural function for MIF.
The three-dimensional crystal structure of human MIF reveals that the protein exists as a homotrimer (Lolis et al.,
Proc. Ass. Am. Phys
. 108:415-419, 1996) and is structurally related to 4-oxalocrotonate tautomerase, 5-(carboxymethyl)-2-hydroxymuconate isomerase, chorismate mutase, and to D-dopachrome tautomerase (Swope et al.,
EMBO J
. 17:3534-3541, 1998; Sugimoto et al.,
Biochemistry
, 38:3268-3279, 1999). Recently, the crystal structure has been reported for the complex formed between human MIF and p-hydroxyphenylpyruvic acid (Lubetsky et al.,
Biochemistry
, 38:7346-54, 1999). It was found that the substrate binds to a hydrophobic cavity at the amino terminus and interacts with Pro-1, Lys-32, and Ile-64 in one of the subunits, and with Tyr-95 and Asn-97 in an adjacent subunit. Similar interactions between murine MIF and (E)-2-fluoro-p-hydroxycinnamate have been reported (Taylor et al.,
Biochemistry
, 38:7444-7452, 1999). Solution studies using NMR provide further evidence of the interaction between p-hydroxyphenylpyruvic acid and Pro-1 in the amino-terminal hydrophobic cavity (Swope et al.,
EMBO J
., 17:3534-3541, 1998).
Mutation studies provide convincing evidence that Pro-I is involved in the catalytic function of MIF. Deletion of Pro-1 or replacement of Pro-1 with Ser (Bendrat et al.,
Biochemistry
, 36:15356-15362, 1997), Gly (Swope et al.,
EMBO J
., 17:3534-3541, 1998), or Phe (Hermanowski-Vosatka et al.,
Biochemistry
, 38:12841-12849, 1999), and addition of an N-terminal peptide tag to Pro-1 (Bendrat et al.,
Biochemistry
, 36:15356-15362, 1997) abrogated the catalytic activity of MIF in assays using L-dopachrome methyl ester and p-hydroxyphenylpyruvic acid. A similar loss in activity was found by inserting Ala between Pro-1 and Met-2 (Lubetsky et al
Al-Abed Yousef
Bucala Richard J.
Mitchell Robert A.
Senter Peter
Bahar Mojdeh
Kelber Steven B.
Piper Rudnick LLP
The Picower Institute for Medical Research
Travers Russell
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