Abstract
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.
MeSH terms
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Animals
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Cell Adhesion / drug effects
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Crystallography, X-Ray
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Dogs
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Graft Rejection / prevention & control
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Humans
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Lymphocyte Function-Associated Antigen-1 / chemistry
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Lymphocyte Function-Associated Antigen-1 / metabolism*
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Mice
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Models, Molecular
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Molecular Structure
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Pneumonia / drug therapy
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Pneumonia / immunology
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / pharmacokinetics
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Thiophenes / pharmacology
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Transplantation, Homologous
Substances
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5-(9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro(4,4)non-7-ylmethyl)-3-thiophenecarboxylic acid
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Lymphocyte Function-Associated Antigen-1
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Spiro Compounds
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Thiophenes