Abstract
We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered two inhibitors with improved oral bioavailability [6 (K(i) = 13 nM, BA = 44%) and 7 (K(i) = 9.8 nM, BA = 42%)]. 6 demonstrated in vivo efficacy in models of inflammation and lymphoma.
MeSH terms
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Adenosine Deaminase Inhibitors*
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Administration, Oral
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Animals
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Biological Availability
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Crystallography, X-Ray
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Dogs
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Drug Design
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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In Vitro Techniques
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Microsomes, Liver / metabolism
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Models, Molecular
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Molecular Structure
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Naphthalenes / chemical synthesis*
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Naphthalenes / chemistry
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Naphthalenes / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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Adenosine Deaminase Inhibitors
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Imidazoles
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Naphthalenes