Molecular model for VLA-4 inhibitors

Details Molecular model for VLA-4 inhibitors Molecular model for VLA-4 inhibitors

1999-01-25

2003-04-22

Brusca, John S. (Department: 1631)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C546S224000, C560S034000, C562S430000, C562S437000, C514S018700

Reexamination Certificate

active

06552216

ABSTRACT:

The present invention relates to a novel pharmacophore model for identifying compounds that are useful for the inhibition, alteration or prevention of the binding of the integrin VLA-4 to its ligands. This invention also relates to methods of discovering molecules which may inhibit VLA-4 binding to its ligands as well as novel molecules which have features which map to the claimed models.
BACKGROUND OF THE INVENTION
In recent years, rational drug design has become a common approach to identifying new drugs in the pharmaceutical industry. This approach requires selecting a protein target molecule which plays a critical role in a physiologically relevant biological pathway. The chemist typically begins with the natural ligand as the lead and modifies it to produce a compound with the desired properties. The natural ligand or substrate of this protein is manipulated to produce an enzyme inhibitor, or an agonist or antagonist for a receptor, depending upon the identified therapeutic need, capitalizing upon knowledge of what is known about the mechanism of action of the protein-ligand complex.
Most cell receptors have a developed pharmacology of agents that act as agonists or antagonists. However, despite extensive pharmacological research and the development of many new methodologies and laboratory techniques, certain receptors, and/or their action still remain elusive and no desirable antagonists have yet been discovered to inhibit or modulate their activity.
Additionally, often certain agonists or antagonists of a particular cell receptor are known, however, there remains a need for methods of identifying new inhibitors, new molecular entities and methods to quickly and effectively determine whether a particular compound possesses a desired pharmacological activity.
Cell adhesion is one of the fundamental mechanisms underlying numerous biological phenomena, such as, for example, the adhesion of hematopoietic cells to endothelial cells, and the subsequent migration of those hematopoietic cells out of the blood vessels and to the site of injury. Thus, cell adhesion is known to play a role in numerous pathologies such as inflammation and immune reactions.
&agr;4&bgr;1 integrin, also known as very late antigen-4 (“VLA-4”), is a leukocyte cell surface receptor that participates in a wide variety of both cell-cell and cell-matrix adhesive interactions. It serves as a receptor for the cytokine-inducible endothelial cell surface protein, vascular cell adhesion molecule-1 (“VCAM-1”), as well as to the extracellular matrix protein fibronectin. Results of several in vivo experiments suggest that the inhibition of VLA-4 dependent cell adhesion may prevent, inhibit or alter several inflammatory and autoimmune pathologies.
In order to identify the minimum active amino acid sequence necessary to bind VL-4, Komriya et al. snthesized a variety of overlapping peptides based on the amino acid sequence of the CS-region (the VLA-4 binding domain) of a particular species of fibronectin. (“The Minimal Essential Sequence for a Major Cell Type-Specifice Adhesion Site (CS1) Within the Alternatively Spilced Type III Conencting Segment Domain of Fibronectin Is Leucine-Aspartic Acid-Valine”, J. Biol. Chem., 266 (23), pp. 15075-79 (1991). They identified an 8-amino acid peptide, SEQ ID NO:1 Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr, as well as two smaller overlapping pentapeptides, SEQ ID NO:2 Glu-Ile-Leu-Asp-Val and SEQ ID NO:3 Leu-Asp-ValPro-Ser, that possessed inhibitory activity against FN-dependent cell adhersion. These results suggested that the tripeptide Leu-Asp-Val was the minimum sequence for cell-adhesion activity. It was later shown that Leu-Asp-Val binds only to lymphocytes that express an activated form of VLA-4, thus casting doubt on the utility of such a peptide in vito. (E. A Wayner et al., “Activation—Dependent Recognition by Hematopoietic Cells of the LDV Sequence in the V Region of Fibronectin”, J. cell. Biol., 116(2), pp. 489-497 (1992)). However, certain larger peptides containing the LDV sequence were subsequently shown to be active in vivo (T. A. Ferguson et al., “Two Intergrin Binding Peptides Abrogate T-Cell-Mediated Immune Responses in Vivo”, Proc. Natl. Acad. Sci. USA, 88, pp. 8072-76 (1991); and S. M. Wahl et al., “Synthetic Fibronectin Peptides Suppress Arthritis in Rats by Interrupting Leukocyte Adhesion and Recruitment”, J. Clin. Invest., 94, pp. 655-62 (1994)).
A cyclic pentapeptide, SEQ ID NO:4 Arg-Cys-Asp-Tpro-Cys (wherein Tpro denotes 4-thioprline), which can inhibit both VLA-4 and VLA-5 adhesion to FN has also been described. (See, e.g., D. M Nowlin et al. “A Novel Cyclic Pentapeptide Inhibits &agr;4&bgr;1 and &agr;5&bgr;1 Integrin-mediated Cell-Adhesion”, J. Biol. Chem., 268(27), pp. 20352-59 (1993); and PCT publication PCT/US91/04862. This pentapeptide was based on the tripeptide sequence Arg-Gly-asp from FN which had been know as a common motif in the recognition site for several extracellular-matrix proteins.
Examples of other VLA-4 inhibitors have been reported, for example, in copending United States patent application U.S. Ser. No. 08/376,372, specifically incorporated by reference herein. U.S. Ser. No. 376,372 describes linear peptidyl compounds containing &bgr;-amino acids which have cell adhesion inhibitory activity. International patent applications WO 94/15958 and WO 92/00995, specifically incorporated by reference, describe cyclic peptide and peptidomimetic compounds with cell adhesion modulating activity. International patent applications WO 93/08823 and WO 92/08464 (specifically incorporated by reference herein) describe guanidinyl-, urea- and thiourea-containing cell adhesion modulating compounds. U.S. Pat. No. 5,260,277 describes guanidinyl cell adhesion modulation compounds, and is also specifically incorporated herein.
As discussed above, it is desirable for several reasons to approach the discovery of new drugs in a rational as opposed to a random manner. Thus, rather than making random modifications to a compound, one can rationally optimize the compound.
Ideally, a three dimensional model of the binding mode of inhibitors to a receptor is sought such that a correlation between the structure of the compound and its effect on biological activity can be derived. Several general approaches exist for determining the three dimensional quantitative structure activity relationships of compounds and their receptors or ligands, including, but not limited to: CATALYST™ (Greene et al., 1994, “Chemical Function queries for Three dimensional database search”, J. Chem. Inf. Comp. Sci., 34, 1297-1308), DISCO (Martin Y. C., et al., 1993, “A Fast new approach to pharmacophore mapping and its application to dopinergic and benzodiazepine agonists”, J. Comp. Aided Mol. Design, 7, 83-102), COMFA (Cramer R. D., 1988, “Comparative molecular field analysis [COMFA] 1. Effect of Shape on Binding of Steroids to Carrier Proteins”, J. Am. Chem. Soc., 110, 5959-5967), Apex3D (Golender, V. E. And Vorpagel, E. R., 1993, “Computer-assisted pharmacophore identification”, Three dimensional-QSAR in Drug Design:Theory, Methods and Applications, ESCOM Science Publ., Netherlands). Once a three dimensional model is built it can be useful in identifying novel compounds. For example, Kiyama et al. were able to identify novel AII antagonists based upon a three dimensional model of known AII inhibitors. (1995, “Novel AII receptor antagonists. Design, synthesis, and in-vitro evaluation of dibenzo[a,d] cycloheptene and dibenzo[b,f] oxepin derivatives. Searching for bioisoteres of biphenyltetrazole using a Three dimensional search technique”, J. Med. Chem., 38, 2728-2741).
In general, there are several fundamental forces which govern the molecular recognition between a drug and its receptor, including, for example, hydrogen-bonding forces, electrostatic and hydrophobic interactions. Until recently most descriptions of inhibitors have been based upon two dimensional atomic topology diagrams which describe chemical structures (e.g. indole ring, carbonyl oxygen). Although these d

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