Integrin antagonists

Title Aza-bridged Bicyclic Amino Acid Derivatives as a4 Integrin 

Assignee Ortho-McNeil Pharmaceutical, Inc. Utility Treatment of Inflammation 

Preparation of ethyl 2-[(phenyl sulfonyl)-2-azabicyclo[2.2.2]oct-3-yl]-3-ene-car-boxylic acid 

A 20 ml 50% solution of benzenesulfonyl isocyanate (0.10 mol) in toluene and 50 ml ethyl glyoxalate in toluene were refluxed 24 hours, then treated with 1,3-cyclohexadiene (0.21 mol), and refluxed an additional 10 hours. Upon cooling, a white precipitate was formed, which was recrystallized in EtOAc, and 19.1 g product isolated as a white solid. 

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Cue D, Southern S, Southern P et al (2000) A non-peptide integrin antagonist can inhibit epithelial cell ingestion of streptococcus pyogenes by blocking a5 31 -fibronectin-Ml protein complexes. Proc Nat Acad Sci 97(6) 2858-2863... 

L., VoLL, G., Haupt, M., Schuster, A., Holzmann, B., and Kessler, H. Synthesis and NMR structure of peptidomi-metic a4/ 7-integrin antagonists. ChemBioChem 2002, 3, 575-578. 

H. N-methylated cyclic RGD peptides as highly active and selective (X,P3 integrin antagonists. J. Med. Chem. 1999, 42, 3033-3040. 

This version of the Wadsworth-Emmons reaction has been used in the scaled-up syntheses of drugs and drug-candidate molecules. For example, it is used to prepare a cinnamate ester that is a starting material for pilot plant synthesis of a potential integrin antagonist.263... 

JW Corbett, NR Graciani, SA Mousa, WF DeGrado. Solid-phase synthesis of a selective oc,(3 integrin antagonist library, (bromomethylphenoxymethyl-polystyrene resin) Bioorg Medicinal Chem 7, 1371, 1997. 

Liu S (2005) 6-Hydrazinonicotinamide Derivatives as Bifunctional Coupling Agents for Tc-Labeling of Small Biomolecules. 252 117-153 Liu S, Robinson SP, Edwards DS (2005) Radiolabeled Integrin Antagonists as Radio-pharmaceuticals for Tumor Radiotherapy. 252 193-216 LiuXY (2005) Gelation with Small Molecules from Formation Mechanism to Nanostructure Architecture. 256 1-37... 

A vitronectin (OvjSs integrin) antagonist, 267268, is currently undergoing clinical trials for the treatment of age-related macular degeneration. 

Kerr, J. S., Slee, A. M., and Mousa, S. A. Small molecule alpha(v) integrin antagonists Novel anticancer agents. Exp. Opin. Invest. Drugs 9 1271-1279, 2000. 

This template removal was encountered during studies to prepare the avP3 integrin antagonist (16). The route that emerged used phenylglycinol as a template in a Reformatsky approach (Scheme 2.25). Unfortunately, lead tetraacetate had to be used to remove this template, so there are still problems to be overcome in this area.93... 

This is indeed the case. In addition to gamma-aminobutyric acid (GABA), opiate and cholecystokinin receptor activities, the benzodiazepine scaffold is also found in muscle relaxants, antidepressants, neuroleptics, hypnotics, NK-1 receptor and vasopressin receptor antagonists, integrin antagonists, farnesyl transferase and phosphodiesterase inhibitors, potassium channel modulators, and others. 

Table 1 Selected experimental integrin antagonists and their corresponding mass spectral data...

In an investigation by Wehner (2), imidazolidine derivatives, (II), were effective as integrin antagonists and used in treating rheumatoid arthritis or allergic diseases. 

Doherty (3), Lin (4), and Hagmann (5) prepared a4(31 and a4(37 integrin antagonists consisting of V-arylsulfonyl-prolines, (III), V-arylsulfonyl aza-bicyclics, (IV), and furanic acid derivatives, (V), respectively, which were effective in treating inflammatory and adhesion pathologies. 

Cycloalkyl alkanoic acids, (HI), prepared by Srinivasan (3) were effective as vitronectin v(33 and/or v(35 receptor integrin antagonists and used to decrease bone resorption and to restore the normal balance of bone forming/resorbing period. 

Cyclic urea derivatives, (IV), prepared by Hutchinson (4) and amine salt derivatives, (V), prepared by Wells (5) were effective as v(i3 and/or v(i5 receptor integrin antagonists and used for inhibiting bone resorption disorders including osteoporosis and periodontal disease. 

Lactone derivatives, (VII), prepared by Ruminiski (6) were selective av(i3 and/or av(35 receptor integrin antagonists and used in treating osteoporosis. 

Shimaoka, M., Salas, A., Yang, W., Weitz-Schmidt, G., and Springer, T. A. (2003a). Small molecule integrin antagonists that bind to the j32 subunit I-like domain and activate signals in one direction and block them in another. Immunity 19, 391-402. 

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