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, 53 (10), 4266-76

2-aminoimidazole Amino Acids as Inhibitors of the Binuclear Manganese Metalloenzyme Human Arginase I

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2-aminoimidazole Amino Acids as Inhibitors of the Binuclear Manganese Metalloenzyme Human Arginase I

Monica Ilies et al. J Med Chem.

Abstract

Arginase, a key metalloenzyme of the urea cycle that converts L-arginine into L-ornithine and urea, is presently considered a pharmaceutical target for the management of diseases associated with aberrant l-arginine homeostasis, such as asthma, cardiovascular diseases, and erectile dysfunction. We now report the design, synthesis, and evaluation of a series of 2-aminoimidazole amino acid inhibitors in which the 2-aminoimidazole moiety serves as a guanidine mimetic. These compounds represent a new class of arginase inhibitors. The most potent inhibitor identified in this study, 2-(S)-amino-5-(2-aminoimidazol-1-yl)pentanoic acid (A1P, 10), binds to human arginase I with K(d) = 2 microM and significantly attenuates airways hyperresponsiveness in a murine model of allergic airways inflammation. These findings suggest that 2-aminoimidazole amino acids represent new leads for the development of arginase inhibitors with promising pharmacological profiles.

Figures

Figure 1
Figure 1
Pathways of L-arginine metabolism.
Figure 2
Figure 2
Stereoview of a simulated annealing gradient map showing 2-aminoimidazole (3.0 σ contour, cyan) bound to human arginase I. Dashed lines indicate manganese coordination (red) and hydrogen bond (green) interactions. Atom color codes: carbon (yellow), oxygen (red), nitrogen (blue), manganese (violet).
Figure 3
Figure 3
Stereoview of a simulated annealing omit map showing the inhibitor 2AH and a sulfate ion bound to human arginase I. The inhibitor (3.0 σ contour, cyan) and sulfate ion (3.5 σ contour, red) were omitted from the structure factor calculation. The sulfate ion coordinates to the manganese ions and accepts hydrogen bonds from the side chain of 2AH. Dashed lines indicate manganese coordination (red) and hydrogen bond (green) interactions. Atom color codes: carbon (yellow), oxygen (red), nitrogen (blue), manganese (violet), sulfur (green).
Figure 4
Figure 4
Stereoview of a simulated annealing omit map showing the inhibitor AHH bound to human arginase I. The inhibitor (3.0 σ contour, cyan) was omitted from the structure factor calculation. Dashed lines indicate manganese coordination (red) and hydrogen bond (green) interactions. Atom color codes: carbon (yellow), oxygen (red), nitrogen (blue), manganese (violet).
Figure 5
Figure 5
A) Kinetic replot of the inhibition of human arginase I by A1P yields Ki = 4 μM. B) Surface plasmon resonance sensorgram showing the binding of A1P to human arginase I; Kd = 2 μM.
Figure 6
Figure 6
Impact of arginase inhibition by A1P in the acute ovalbumin (OVA)-sensitization and -challenge murine model of allergic airways inflammation. A) A1P attenuated significantly the maximum total lung resistance (R) evoked by methacholine challenge in mice sensitized to OVA and challenged with nebulized vehicle (OVA/PBS), or OVA (OVA/OVA and OVA/OVA A1P). B) A1P also notably decreased the maximum methacholine-induced increase in central airways responsiveness (RN) in the same animal model. Values are expressed as the means ± SE (n = 12/group) (*P < 0.05; ***P < 0.0001 to OVA/PBS; ##P < 0.01 to OVA/OVA).
Scheme 1
Scheme 1
Synthesis of the Key Intermediates 4 and 6
Scheme 2
Scheme 2
Synthesis of A1P
Scheme 3
Scheme 3
Synthesis of APP
Scheme 4
Scheme 4
Synthesis of A4P

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