Selective Substrate-Based Inhibitors of Mammalian Dimethylarginine Dimethylaminohydrolase
- 14 June 2005
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 48 (14) , 4670-4678
- https://doi.org/10.1021/jm050187a
Abstract
The enzyme DDAH metabolizes methylarginines that are inhibitors of nitric oxide synthase (NOS). Substrate-based inhibitors of mammalian DDAH have been synthesized, with optimization to give selective inhibition of DDAH with no significant direct effect on NOSs. These are the first examples of reversible DDAH inhibitors with significant activity and selectivity. In vivo administration increases plasma ADMA levels, giving proof of concept that these inhibitors can be used to probe the physiological effects of DDAH inhibition, with potential for pharmaceutical use of DDAH inhibitors in diseases where excess NO production is implicated.Keywords
This publication has 14 references indexed in Scilit:
- Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotypeBiochemical and Biophysical Research Communications, 2003
- Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine DimethylaminohydrolaseArteriosclerosis, Thrombosis, and Vascular Biology, 2003
- Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric DimethylarginineCirculation Research, 2003
- Blocking NO synthesis: how, where and why?Nature Reviews Drug Discovery, 2002
- Endogenous Methylarginines Regulate Neuronal Nitric-oxide Synthase and Prevent Excitotoxic InjuryJournal of Biological Chemistry, 2002
- Determination of Arginine, Asymmetric Dimethylarginine, and Symmetric Dimethylarginine in Human Plasma and Other Biological Samples by High-Performance Liquid ChromatographyAnalytical Biochemistry, 2002
- Regulation of macrophage nitric oxide synthesis by endothelial cells: a role for NG,NG‐dimethylarginineActa Physiologica Scandinavica, 1999
- Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminasesBiochemical Journal, 1999
- Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolaseBritish Journal of Pharmacology, 1996
- NG-allyl- and NG-cyclopropyl-L-arginine: two novel inhibitors of macrophage nitric oxide synthaseJournal of Medicinal Chemistry, 1992