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Squaric acid derivatives as VLA-4 integrin antagonists. 2002

John R Porter, and Sarah C Archibald, and Kirstie Childs, and David Critchley, and John C Head, and Janeen M Linsley, and Ted A H Parton, and Martyn K Robinson, and Anthony Shock, and Richard J Taylor, and Graham J Warrellow, and Rikki P Alexander, and Barry Langham
Celltech R&D Ltd, 216 Bath Road, Slough SL1 4EN, UK. john.porter@celltechgroup.com

SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described.

UI MeSH Term Description Entries
D008657 Metabolic Clearance Rate Volume of biological fluid completely cleared of drug metabolites as measured in unit time. Elimination occurs as a result of metabolic processes in the kidney, liver, saliva, sweat, intestine, heart, brain, or other site. Total Body Clearance Rate,Clearance Rate, Metabolic,Clearance Rates, Metabolic,Metabolic Clearance Rates,Rate, Metabolic Clearance,Rates, Metabolic Clearance
D003503 Cyclobutanes Four carbon cycloparaffin cyclobutane (the structural formula (CH2)4) and its derivatives.
D000588 Amines A group of compounds derived from ammonia by substituting organic radicals for the hydrogens. (From Grant & Hackh's Chemical Dictionary, 5th ed) Amine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D016023 Integrins A family of transmembrane glycoproteins (MEMBRANE GLYCOPROTEINS) consisting of noncovalent heterodimers. They interact with a wide variety of ligands including EXTRACELLULAR MATRIX PROTEINS; COMPLEMENT, and other cells, while their intracellular domains interact with the CYTOSKELETON. The integrins consist of at least three identified families: the cytoadhesin receptors (RECEPTORS, CYTOADHESIN), the leukocyte adhesion receptors (RECEPTORS, LEUKOCYTE ADHESION), and the VERY LATE ANTIGEN RECEPTORS. Each family contains a common beta-subunit (INTEGRIN BETA CHAINS) combined with one or more distinct alpha-subunits (INTEGRIN ALPHA CHAINS). These receptors participate in cell-matrix and cell-cell adhesion in many physiologically important processes, including embryological development; HEMOSTASIS; THROMBOSIS; WOUND HEALING; immune and nonimmune defense mechanisms; and oncogenic transformation. Integrin
D016029 Receptors, Very Late Antigen Members of the integrin family appearing late after T-cell activation. They are a family of proteins initially identified at the surface of stimulated T-cells, but now identified on a variety of cell types. At least six VLA antigens have been identified as heterodimeric adhesion receptors consisting of a single common beta-subunit and different alpha-subunits. Receptors, VLA,VLA Protein Complex,Receptor, Very Late Antigen,Receptors, Very Late Activation Antigen,VLA Activation Antigens,VLA Differentiation Antigens,VLA Receptors,Very Late Activation Antigen Receptors,Very Late Antigen Receptors,Activation Antigens, VLA,Antigens, VLA Activation,Antigens, VLA Differentiation,Differentiation Antigens, VLA,Protein Complex, VLA
D016201 Receptors, Lymphocyte Homing Cell surface glycoproteins on lymphocytes and other leukocytes that mediate adhesion to specialized blood vessels called high endothelial venules. Several different classes of lymphocyte homing receptors have been identified, and they appear to target different surface molecules (addressins) on high endothelial venules in different tissues. The adhesion plays a crucial role in the trafficking of lymphocytes. Hermes Antigen Family,Homing Receptors, T-Cell,Lymphocyte Homing Receptors,Homing Receptor, Lymph Node,Lymph Node Homing Receptor,Receptor, Lymph Node Homing,Antigen Family, Hermes,Homing Receptors, Lymphocyte,Homing Receptors, T Cell,Receptors, T-Cell Homing,T-Cell Homing Receptors
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D018926 Anti-Allergic Agents Agents that are used to treat allergic reactions. Most of these drugs act by preventing the release of inflammatory mediators or inhibiting the actions of released mediators on their target cells. (From AMA Drug Evaluations Annual, 1994, p475) Anti-Allergic,Anti-Allergic Agent,Anti-Allergy Drug,Antiallergic,Antiallergic Agent,Antiallergic Drug,Anti-Allergics,Anti-Allergy Drugs,Antiallergic Agents,Antiallergic Drugs,Antiallergics,Antiallergy Agents,Agent, Anti-Allergic,Agent, Antiallergic,Agents, Anti-Allergic,Agents, Antiallergic,Agents, Antiallergy,Anti Allergic,Anti Allergic Agent,Anti Allergic Agents,Anti Allergics,Anti Allergy Drug,Anti Allergy Drugs,Drug, Anti-Allergy,Drug, Antiallergic,Drugs, Anti-Allergy,Drugs, Antiallergic

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