Reverse-turn mimetics and methods relating thereto

Details Reverse-turn mimetics and methods relating thereto Reverse-turn mimetics and methods relating thereto

1999-09-01

2001-09-25

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S221000, C514S249000, C530S317000, C530S323000, C530S333000, C540S469000, C540S502000, C544S236000

Reexamination Certificate

active

06294525

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to reverse-turn mimetics, including inhibitors of cell adhesion-mediated disease, as well as to a chemical library of reverse-turn mimetics.
BACKGROUND OF THE INVENTION
In the search for new therapeutics, the pharmaceutical industry has increasingly turned to the techniques of combinatorial chemistry, parallel synthesis, and high throughput screening to generate and optimize lead compounds (
Combinatorial Chemistry and Molecular Diversity in Drug Discovery
Gordon and Kerwin, Eds., John Wiley & Sons, New York, 1998
; The Combinatorial Index
Bunin, Academic Press, New York, 1998
; A Practical Guide to Combinatorial Chemistry
Czarnik and DeWitt, Eds., American Chemical Society, Washington, D.C., 1997
; High Throughput Screening: The Discovery of Bioactive Substances
Devlin, Marcel Dekker, New York, 1997). These techniques can produce libraries of hundreds to hundreds of thousands—or more—of compounds in a short period of time. The libraries are then assayed against targets of interest, often in a highly automated fashion, to identify biologically active compounds. Libraries, which are simply collections of compounds, may be tightly focused around a specific template or contain a variety of unrelated templates. In many instances, the diversity of the library is an important design parameter.
On a basic level, the number of points of diversity on a molecular template or scaffold, i.e., the number of positions at which variation in structure may be introduced, has a practical effect on the ease with which large libraries may be created. When combinatorial techniques are employed, a template that contains three points of diversity would give rise to 8000 compounds if 20 components are used to derivatize each point and a total of 60 reactions are carried out (20
3
). However, a template with four points of diversity will yield over 50,000 compounds when 15 components are used at each point in a total of 60 reactions (15
4
). In general, large libraries may be created more efficiently on templates allowing more possibilities for derivatization.
In order to increase the chances of finding a biologically active compound for a particular target, it is usually desirable to synthesize a library spanning a range of both conformational space and chemical properties such as hydrophobicity and hydrogen bonding ability. At the same time, low molecular weight is often a goal as well, since compounds of less than 500 Daltons are perceived as more likely to have favorable pharmacokinetic properties in relation to higher molecular weight compounds. All these characteristics point to the continuing need for small compact templates that support a wide range of substituents and which are simple to synthesize.
Reverse-turns comprise one of three classes of protein secondary structure and display three (gamma-turn), four (beta-turns), or more (loops) amino acid side chains in a fixed spatial relationship to each other. Turns have proven important in molecular recognition events (Rose et al.,
Advances in Protein Chemistry
37:1-109, 1985) and have engendered a burgeoning field of research into small molecule mimetics of them (e.g., Hanessian et al.,
Tetrahedron
53:12789-12854, 1997). Many mimetics have either been external turn-mimetics which do not allow for the display of all the physiologically relevant side-chains (e.g., Freidinger et al.,
Science
210:656-8, 1980) or small, conformationally mobile cyclic peptide derivatives (e.g., Viles et al.,
Eur. J Biochem
. 242:352-62, 1996). However, non-peptide compounds have been developed which closely mimic the secondary structure of reverse-turns found in biologically active proteins or peptides. For example, U.S. Pat. Nos. 5,475,085, 5,670,155 and 5,672,681 to Kahn and published PCT WO94/03494 to Kahn all disclose conformationally constrained, non-peptidic compounds which mimic the three-dimensional structure of reverse-turns. More recently, U.S. Pat. No. 5,929,237 to Kahn, and published PCT WO97/15577 to Kahn and PCT WO98/49168 to Kahn et al. disclosed additional, highly constrained bicyclic heterocycles as reverse-turn mimetics. Nevertheless, as no one template can mimic every type of turn, there remains a need in the art for additional reverse-turn templates.
Cell adhesion is critical to the viability of living organisms. Adhesion holds multicellular tissues together and directs embryonic development. It plays important roles in wound healing, eradication of infection and blood coagulation. Integrins are a family of cell surface proteins intimately involved in all of these functions. They have been found in nearly every type of human cell except red blood cells. Abnormalities in integrin function contribute to a variety of disorders including inflammatory diseases, heart attack, stroke, and cancer.
Integrins consist of heterodimers of &agr; and &bgr; subunits, non-covalently bound to each other. These cell surface receptors extend through the cell membrane into the cytoplasm. At least 15 different &agr; and 9 different &bgr; subunits are known. However, because most &agr; proteins associate with only a single &bgr; there are about 21 known integrin receptors. On the cell surface the heads of the two subunits contact each other to form a binding surface for extracellular protein ligands, allowing attachment to other cells or to the extracellular matrix. The affinity of these receptors may be regulated by signals from outside or within the cell. For example, recruitment of leukocytes to the site of injury or infection involves a series of adhesive interactions. Weak interaction between endothelial and leukocyte selectins and carbohydrates mediate transient adhesion and rolling of the leukocyte along the vessel wall. Various chemokines and other trigger factors released by the site of inflammation serve as signals to activate integrins from a quiescent to a high affinity state. These activated integrins then bind their cognate ligands on the surface of the endothelial cells, resulting in strong adhesion and flattening of the leukocyte. Subsequently the leukocyte migrates through the endothelium into the tissue below.
Integrin &agr;
4
&bgr;
1
mediates cell adhesion primarily through binding to either vascular cell adhesion molecule-1 (VCAM-1) or an alternatively spliced variant of fibronectin containing the type III connecting segment (IIICS). A variety of cells involved in inflammation express &agr;
4
&bgr;
1
, including lymphocytes, monocytes, basophils and eosinophils, but not neutrophils. Monoclonal antibodies to the &agr;
4
subunit have been used to validate &agr;
4
-containing integrins as potential therapeutic targets in animal models of rheumatoid arthritis (Barbadillo et al.,
Springer Semin Immunopathol
. 16:427-36, 1995; Issekutz et al.,
Immunology
88:569-76, 1996), acute colitis (Podolsky et al.,
J Clin. Invest
. 92:372-80, 1993), multiple sclerosis (Yednock et al.,
Nature
356:63-6, 1992), asthma (Abraham et al.,
J Clin. Invest
. 93:776-87, 1994) U.S. Pat. No. 5,871,734) and diabetes (Tsukamoto et al.,
Cell Immunol
. 165:193-201, 1995). More recently, low molecular weight peptidyl derivatives have been produced as competitive inhibitors of &agr;
4
&bgr;
1
and one has been shown to inhibit allergic airway responses in sheep (Lin et al.,
J Med. Chem
. 42:920-34, 1999).
It has been shown that a key sequence in IIICS involved in binding to &agr;
4
&bgr;
1
is the 25 residue peptide CS1, and within that sequence the minimally recognized motif is the tripeptide, LDV. A similar sequence, IDS, has been implicated in the binding of VCAM-1 to &agr;
4
&bgr;
1
. X-ray crystal structures of an N-terminal two-domain fragment of VCAM-1 show that the IDS sequence is part of an exposed loop linking two beta-strands (Jones et al.,
Nature
373:539-44, 1995; Wang et al.,
Proc. Natl. Acad. Sci. USA
92:5714-8, 1995). Cyclic peptides and derivatives thereof which adopt reverse-turn conformations have proven to be inhibitors of VCAM-1 binding to &agr;
4
&bgr;
1
(WO 96/00581; WO 96/06108; D

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