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Molecules 2016, 21(5), 615; doi:10.3390/molecules21050615

Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development

Department of Clinical Pharmacology, School of Medicine, Flinders University, Bedford Park, Adelaide 5042, Australia
These authors contributed equally to this work.
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Author to whom correspondence should be addressed.
Academic Editors: Jean Jacques Vanden Eynde and Sylvain Rault
Received: 9 February 2016 / Revised: 19 April 2016 / Accepted: 4 May 2016 / Published: 11 May 2016

Abstract

Dimethylarginine dimethylaminohydrolase (DDAH) is a highly conserved hydrolytic enzyme found in numerous species, including bacteria, rodents, and humans. In humans, the DDAH-1 isoform is known to metabolize endogenous asymmetric dimethylarginine (ADMA) and monomethyl arginine (l-NMMA), with ADMA proposed to be a putative marker of cardiovascular disease. Current literature reports identify the DDAH family of enzymes as a potential therapeutic target in the regulation of nitric oxide (NO) production, mediated via its biochemical interaction with the nitric oxide synthase (NOS) family of enzymes. Increased DDAH expression and NO production have been linked to multiple pathological conditions, specifically, cancer, neurodegenerative disorders, and septic shock. As such, the discovery, chemical synthesis, and development of DDAH inhibitors as potential drug candidates represent a growing field of interest. This review article summarizes the current knowledge on DDAH inhibition and the derived pharmacokinetic parameters of the main DDAH inhibitors reported in the literature. Furthermore, current methods of development and chemical synthetic pathways are discussed. View Full-Text
Keywords: dimethylarginine dimethylaminohydrolase; arginine; nitric oxide; asymmetric dimethylarginine; monomethyl arginine; enzyme inhibitors; organic synthesis dimethylarginine dimethylaminohydrolase; arginine; nitric oxide; asymmetric dimethylarginine; monomethyl arginine; enzyme inhibitors; organic synthesis
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Murphy, R.B.; Tommasi, S.; Lewis, B.C.; Mangoni, A.A. Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development. Molecules 2016, 21, 615.

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