title: Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development.
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.
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Bedford Park, Adelaide 5042, Australia. rhys.murphy@flinders.edu.au.
authors.forename: Rhys B
authors.initials: RB
authors.lastname: Murphy
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Bedford Park, Adelaide 5042, Australia. sara.tommasi@flinders.edu.au.
authors.forename: Sara
authors.initials: S
authors.lastname: Tommasi
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Bedford Park, Adelaide 5042, Australia. ben.lewis@flinders.edu.au.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Lewis
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University, Bedford Park, Adelaide 5042, Australia. arduino.mangoni@flinders.edu.au.
authors.forename: Arduino A
authors.initials: AA
authors.lastname: Mangoni
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000818:Animals; D055808:Drug Discovery; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans
chemical_list: D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: arginine; asymmetric dimethylarginine; dimethylarginine dimethylaminohydrolase; enzyme inhibitors; monomethyl arginine; nitric oxide; organic synthesis