alpha-Keto amide inhibitors of aminopeptidases.
The design and synthesis of 3-amino-2-oxo-4-phenylbutanoic acid amides (alpha-keto amides), a new class of aminopeptidase inhibitor, are described. These compounds, illustrated by the Phe-Leu analogue 2, are effective inhibitors of arginyl aminopeptidase (Ki = 1.5 microM), cytosol aminopeptidase (Ki = 1.0 microM), and microsomal aminopeptidase (Ki = 2.5 microM). The ketone carbonyl of the alpha-keto amide was found to hydrate readily in an aqueous DMSO solution, due to the electron-withdrawing effect of the neighboring amide group. A mechanism of inhibition is proposed for the alpha-keto amides that is similar to that proposed for the structurally related aminopeptidase inhibitor bestatin and its analogues, wherein the inhibitor may interact with the S1'-S2' subsite of the enzyme rather than the S1-S1' subsite. Like bestatin, the alpha-keto amides are slow-binding inhibitors of all three enzymes.
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School of Pharmacy, University of Wisconsin-Madison 53706.
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D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship
D000577:Amides; D004791:Enzyme Inhibitors; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex